PG-type, 1,9-lactones

ABSTRACT

The present invention provides novel 1,9 lactones of prostaglandin-type free acids and a process for their preparation. These lactones are useful for the same pharmacological purposes as the corresponding prostaglandin-type free acids.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of copending application Ser.No. 589,724, filed June 23, 1975, now abandaned.

BACKGROUND OF THE INVENTION

This invention provides novel compositions of matter.

Particularly this invention provides novel lactones of some of the knownprostaglandins or prostaglandin analogs.

The known prostaglandins include the PGE compounds, e.g. prostaglandinE₁ (PGE₁), prostaglandin E₂ (PGE₂), prostaglandin E₃ (PGE₃), anddihydroprostaglandin E₁ (dihydro-PGE₁).

The known prostaglandins include PGF.sub.α compounds, e.g. prostaglandinF₁α (PGF₁α), prostaglandin F₂α (PGF₂α), prostaglandin F₃α (PGF₃α), anddihydroprostaglandin F₁α (dihydro-PGF₁α).

The known prostaglandins include PGF.sub.β compounds, e.g. prostaglandinF₁β (PGF₁β), prostaglandin F₂β (PGE₂β), prostaglandin F₃β (PGE₃β), anddihydroprostaglandin F₁β (dihydro-PGF₁β).

The known prostaglandins include PGA compounds, e.g. prostaglandin A₁(PGA₁), prostaglandin A₂ (PGA₂), prostaglandin A₃ (PGA₃), anddihydroprostaglandin A₁ (dihydro-PGA₁).

the known prostaglandins include PGB compounds, e.g. prostaglandin B₁(PGB₁), prostaglandin B₂ (PGB₂), prostaglandin B₃ (PGB₃), anddihydroprostaglandin B₁ (dihydro-PGB₁).

Each of the above mentioned known prostaglandins (PG's) is a derivativeof prostanoic acid which has the following structure and carbon atomnumbering ##STR1## See, for example, Bergstrom et al., Pharmacol. Rev.20, 1 (1968), and references cited therein. A systematic name forprostanoic acid is 7-[(2β-octyl)-cyclopent-1α-yl]heptanoic acid.

PGE₁ has the following structure: ##STR2##

PGE₂ has the following structure: ##STR3##

PGE₃ has the following structure: ##STR4##

Dihydro-PGE₁ has the following structure: ##STR5##

PGF₁α has the following structure: ##STR6##

PGF₂α has the following structure: ##STR7##

PGF₃α has the following structure: ##STR8##

Dihydro-PGF₁α has the following structure: ##STR9##

PGF₁β has the following structure: ##STR10##

PGF₂β has the following structure: ##STR11##

PGF₃β has the following structure: ##STR12##

Dihydro-PGF₁β has the following structure: ##STR13##

PGA₁ has the following structure: ##STR14##

PGA₂ has the following structure: ##STR15##

PGA₃ has the following structure: ##STR16##

Dihydro-PGA₁ has the following structure: ##STR17##

PGB₁ has the following structure: ##STR18##

PGB₂ has the following structure: ##STR19##

PGB₃ has the following structure: ##STR20##

Dihydro-PGB₁ has the following structure: ##STR21##

In the above formulas, as well as in the formulas hereinafter given,broken line attachments to the cyclopentane ring indicate substituentsin alpha configuration i.e., below the plane of the cyclopentane ring.Heavy solid line attachments to the cyclopentane ring indicatesubstituents in beta configuration, i.e., above the plane of thecyclopentane ring. The use of wavy lines (˜) herein will representattachment of substituents in either the alpha or beta configuration orattachment in a mixture of alpha and beta configurations.

The side-chain hydroxy at C-15 in the above formulas is in Sconfiguration. See, Nature 212, 38 (1966) for discussion of thestereochemistry of the prostaglandins. Expressions such as C-9, C-11,C-15, and the like, refer to the carbon atom in the prostaglandin analogwhich is in the position corresponding to the position of the samenumber in prostanoic acid.

Molecules of the known prostaglandins each have several centers ofasymmetry, and can exist in racemic (optically inactive) form and ineither of the two enantiomeric (optically active) forms, i.e. thedextrorotatory and levorotatory forms. As drawn, the above formulas eachrepresent the particular optically active form of the prostaglandin asis obtained from mammalian tissues, for example, sheep vesicular glands,swine lung, or human seminal plasma, from carbonyl and/or double bondreduction of the prostaglandin so obtained. See, for example, Bergstromet al., cited above. The mirror image of each of these formulasrepresents the other enantiomer of that prostaglandin. The racemic formof a prostaglandin contains equal numbers of both enantiomericmolecules, and one of the above formulas and the mirror image of thatformula is needed to represent correctly the corresponding racemicprostaglandin.

For convenience hereinafter, use of the term, prostaglandin or "PG" willmean the optically active form of that prostaglandin thereby referred towith the same absolute configuration as PGE₁ obtained from mammaliantissues. When reference to the racemic form of one of thoseprostaglandins is intended, the word "racemic" or "d1" will precede theprostaglandin name.

The term "prostaglandin-type" (PG-type) compound, as used herein, refersto any cyclopentane derivative herein which is useful for at least oneof the same pharmacological purposes as the prostaglandins, as indicatedherein.

The term prostaglandin-type intermediate, as used herein, refers to anycyclopentane derivative useful in preparing a prostaglandin-typecompound.

The formulas, as drawn herein, which depict a prostaglandin-typecompound or an intermediate useful in preparing a prostaglandin-typecompound, each represent the particular stereoisomer of theprostaglandin-type compound which is of the same relative stereochemicalconfiguration as a corresponding prostaglandin obtained from mammaliantissues, or the particular stereoisomer of the intermediate which isuseful in preparing the above stereoisomer of the prostaglandin-typecompounds.

The term "prostaglandin analog", as used herein, represents thatstereoisomer of a prostaglandin-type compound which is of the samerelative stereochemical configuration as a corresponding prostaglandinobtained from mammalian tissues, a mixture comprising that stereoisomerand the enantiomer thereof, or the enantiomer thereof. In particular,where a formula is used to depict a prostaglandin- type compound herein,the term prostaglandin analog refers to the compound of that formula, ora mixture comprising that compound and the enantiomer thereof.

The term "prostaglandin-type lactone" as used herein refers to a 1,9-;1,11-; or 1,15-lactone of a prostaglandin or prostaglandin analog, butonly to the extent that the C-9, C-11, or C-15 position, respectively,is hydroxylated and thus capable of lactone formation with the PGcarboxyl. For example, as applied to a PGE-type compound (e.g. PGE₂) theterm "prostaglandin-type lactone" refers only to a 1,11- or1,15-lactone. Further, where a formula is used to depict aprostaglandin-type lactone herein, or a prostaglandin analog from whichthe prostaglandin-type lactone is prepared, the term "prostaglandin-typelactone" refers to the compound of that formula (or the lactone preparedtherefrom) or a mixture comprising that compound (or the lactoneprepared therefrom) and the enantiomer thereof.

The various PG's named above, their esters, acylates andpharmacologically acceptable salts, are extremely potent in causingvarious biological responses. For that reason, these compounds areuseful for pharmacological purposes. See, for example, Bergstrom et al.,Pharmacol. Rev. 20, 1 (1968) and references cited therein.

For the PGE compounds these biological responses include:

a. stimulating smooth muscle (as shown by tests, for example, on guineapig ileum, rabbit duodenum, or qerbil colon);

b. affecting lipolytic activity (as shown by antagonism of epinephrineinduced release of glycerol from isolated rat fat pads);

c. inhibiting gastric secretion and reducing undesirablegastrointestinal effects from systematic administration of prostaglandinsynthetase inhibitors;

d. controlling spasm and facilitating breathing in asthmatic conditions;

e. decongesting nasal passages;

f. decreasing blood platelet adhesion (as shown by platelet to glassadhesiveness) and inhibiting blood platelet aggregation and thrombusformation induced by various physical stimuli (e.g., arterial injury) orchemical stimuli (e.g., ATP, ADP, serotinin, thrombin, and collagen);

g. affecting the reproductive organs of mammals as labor inducers,abortifacients, cervical dilators, regulators of the estrus, andregulators of the menstrual cycle; and

h. accelerating growth of epidermal cells and keratin in animals.

For the PGF.sub.α compound these biological responses include:

a. stimulating smooth muscle (as shown by tests on guinea pig ileum,rabbit duodenum, or gerbil colon);

b. inhibiting gastric secretion and reducing undesirablegastrointestinal effects from systemic administration of prostaglandinsynthetase inhibitors;

c. decongesting nasal passages;

d. decreasing blood platelet adhesion (as shown by platelet to glassadhesiveness) and inhibiting blood platelet aggregation and thrombusformation induced by various physical stimuli (e.g., arterial injury) orchemical stimuli (e.g., ADP, ATP, serotinin, thrombin, and collagen);and

e. affecting the reproductive organs of mammals as labor inducers,abortifacients, cervical dilators, regulators of the estrus, andregulators of the menstral cycle.

For the PGF.sub.α compounds these biological response include:

a. stimulating smooth muscle (as shown by tests on guinea pig ileum,rabbit duodenum, or gerbil colon);

b. inhibiting gastric secretion and reducing undesirablegastrointestinal effects from systematic administration of prostaglandinsynthetase inhibitors;

c. controlling spasm and facilitating breathing in asthmatic conditions;

d. decongesting nasal passages;

e. decreasing blood platelet adhesion (as shown by platelet to glassadhesiveness) and inhibiting blood platelet aggregation and thrombisformation induced by various physical stimuli (e.g., arterial injury) orchemical stimuli (e.g., ADP, ATP, serotinin, thrombin, and collagen);and

f. affecting the reproductive organs of mammals as labor inducers,abortifacients, cervical dilators, regulators of the estrus, andregulators of the menstrual cycle.

For the PGA compounds these biological responses include:

a. stimulating smooth muscle (as shown by tests on quinea pig ileum,rabbit duodenum, or gerbil colon);

b. inhibiting gastric secretion and reducing undesirablegastrointestinal effects from systematic administration of prostaglandinsynthetase inhibitors;

d. controlling spasm and facilitating breathing in asthmatic conditions;

d. decongesting nasal passages; and

e. increasing kidney blood flow.

For the PGB compounds these biological responses include:

a. stimulating smooth muscle (as shown by tests on guinea pig ileum,rabbit duodenum, or gerbil colon); and

b. accelerating growth of epidermal cells and keratin in animals.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdiseases and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys.

The compounds so cited above as extremely potent in causing stimulationof smooth muscle are also highly active in potentiating other knownsmooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin,and the various ergot alkaloids including derivatives and analogsthereof. Therefore, these compounds for example, are useful in place ofor in combination wth less than usual amounts of these known smoothmuscle stimulators, for example, to relieve the symptoms of paralyticileus, or to control or prevent atonic uterine bleeding after abortionor delivery, to aid in expulsion of the placenta, and during thepuerperium. For the latter purpose, the prostaglandin is administered byintravenous infusion immediately after abortion or delivery at a dose inthe range about 0.01 to about 50μg. per kg. of body weight per minuteuntil the desired effect is obtained. Subsequent doses are given byintravenous, subcutaneous, or intramuscular injection or infusion duringpuerperium in the range 0.01 to 2 mg. per kg. of body weight per day,the exact dose depending on the age, weight, and condition of thepatient or animal.

As mentioned above, the PGE compounds are potent antagonists ofepinephrine-induced mobilization of free fatty acids. For this reason,this compound is useful in experimental medicine for both in vitro andin vivo studies in mammals, including man, rabbits, and rats, intendedto lead to the understanding, prevention, symptom alleviation, and cureof diseases involving abnormal lipid mobilization and high free fattyacid levels, e.g. diabetes mellitus, vascular diseases, andhyperthyroidism.

The prostaglandins so cited above as useful in mammals, including manand certain useful animals, e.g., dogs and pigs, to reduce and controlexcessive gastric secetion, therby reduce or avoid gastrointestinalulcer formation, and accelerate the healing of such ulcers alreadypresent in the gastrointestinal tract. For this purpose, these compoundsare injected or infused intravenously, subcutaneously, orintramuscularly in an infusion dose range about 0.1 to about 500 μg. perkg. of body weight per minute, or in a total daily dose by injection orinfusion in the range about 0.1 to about 20 mg. per kg. of body weightper day, the exact dose depending on the age, weight, and condition ofthe patient or animal, and on the frequency and route of administration.

These compounds are also useful in reducing the undesirablegastrointestinal effects resulting from systemic administration ofanti-inflammatory prostaglandin synthetase inhibitors, and are used forthat purpose by concomitant administration of the prostaglandin and theanti-inflammatory prostaglandin synthetase inhibitor. See Partridge etal., U.S. Pat. No. 3,781,429, for a disclosure that the ulcerogeniceffect induced by certain non-steroidal anti-inflammatory agents in ratsis inhibited by concomitant oral administration of certainprostaglandins of the E and A series, including PGE₁, PGE₂, PGE₃,13,14-dihydro-PGE₁, and the corresponding 11-deoxy-PGE and PGAcompounds. Prostaglandins are useful, for example, in reducing theundesirable gastrointestinal effects resulting from systemicadministration of indomethacin, phenylbutazone, and aspirin. These aresubstances specifically mentioned in Partridge et al. as non-steroidal,anti-inflammatory agents. These are also known to be prostaglandinsynthetase inhibitors.

The anti-flammatory synthetase inhibitor, for example, indomethacin,aspirin, or phenylbutazone is administered in any of the ways known inthe art to alleviate an inflammatory condition, for example, in anydosage regimen and by any of the known routes of systemicadministration.

The prostaglandin is administered along with the anti-inflammatoryprostaglandin synthetase inhibitor either by the same route ofadministration or by a different route. For example, if theanti-inflammatory substance is being administered orally, theprostaglandin is also administered orally or, alternatively, isadministered rectally in the form of a suppository or, in the case ofwomen, vaginally in the form of a suppository or a vaginal device forslow release, for example as described in U.S. Pat. No. 3,545,439.Alternatively, if the anti-inflammatory substance is being administeredrectally, the prostaglandin is also administered rectally, or,alternatively, orally or, in the case of women, vaginally. It isespecially convenient when the administration route is to be the samefor both anti-inflammatory substance and prostaglandin, to combine bothinto a single dosage form.

The dosage regimen for the prostaglandin in accord with this treatmentwill depend upon a variety of factors, including the type, age, weight,sex, and medical condition of the mammal, the nature and dosage regimenof the anti-inflammatory synthetase inhibitor being administered to themammal, the sensitivity of the particular individual mammal to theparticular synthetase inhibitor with regard to gastrointestinal effects,and the particular prostaglandin to be administered. For example, notevery human in need of an anti-inflammatory substance experienced thesame adverse gastrointestinal effects when taking the substance. Thegastrointestinal effects will frequently vary substantially in kind anddegree. But it is within the skill of the attending physician orveterinarian to determine that administration of the anti-inflammatorysubstance is causing undesirable gastrointestinal effects in the humanor animal subject and to prescribe an effective amount of theprostaglandin to reduce and then substantially to eliminate thoseundesirable effects.

The prostaglandins so cited above as useful in the treatment of asthma,are useful, for example, as bronchodilators or as inhibitors ofmediators, such as SRS-A, and histamine which are released from cellsactivated by an antigen-antibody complex. Thus, these compounds controlspasm and facilitate breathing in conditions such as bronchial asthma,bronchitis, bronchiectasis, pneumonia, bronchitis, bronchiectasis,pneumonia, and emphysema. For these purposes, the compounds areadministered in a variety of dosage forms, e.g., orally in the form oftablets, capsules, or liquids; rectally in the form of suppositories;parenterally; subcutaneously; or intramuscularly; with intravenousadministration being preferred in emergency situations; by inhalation inthe form of aerosols or solutions for nebulizers; or by insufflation inthe form of powder. Doses in the range of about 0.1 to 5 mg. per kg. ofbody weight are used 1 to 4 times a day, the exact dose depending on theage, weight, and condition of the patient and on the frequency and routeof administration. For the above use these prostaglandins can becombined advantageously with other antiasthmatic agents, such assympathomimerics (isoproterenol, phenylephrine, epinephrine, etc.);xanthine derivatives (theophylline and aminophylline); andcorticosteroids (ACTH and prednisolone). Regarding use of thesecompounds see M. E. Rosenthale, et al., U.S. Pat. No. 3,644,638.

The prostaglandins so cited above as useful in mammals, including man,as nasal decongestants are used for this purpose, in a dose range ofabout 10 μg. to about 10 mg. per ml. of a pharmacologically suitableliquid vehicle or as an aerosol spray, both for topical application.

The prostaglandins so cited above as useful whenever it is desired toinhibit platelet aggregation, reduce the adhesive character ofplatelets, and remove or prevent the formation of thrombi in mammals,including man, rabbits, and rats. For example, these compounds areuseful in the treatment and prevention of myocardial infarcts, to treatand prevent post-operative thrombosis, to promote patency of vasculargrafts following surgery, and to treat conditions such asatherosclerosis, arteriosclerosis, blood clotting defects due tolipemia, and other clinical conditions in which the underlying etiologyis associated with lipid imbalance or hyperlipidemia. For thesepurposes, these compounds are administered systemically, e.g.,intravenously, subcutaneously, intramuscularly, and in the form ofsterile implants for prolonged action. For rapid response, especially inemergency situations, the intravenous route of administration ispreferred. Doses in the range about 0.005 to about 20 mg. per kg. ofbody weight per day are used, the exact dose depending on the age,weight, and condition of the patient or animal, and on the frequency androute of administration.

These compounds are further useful as additives to blood, bloodproducts, blood substitutes, or other fluids which are used inartificial extracorporeal circulation or perfusion of isolated bodyportions, e.g., limbs and organs, whether attached to the original body,detached and being preserved or prepared for transplant, or attached toa new body. During these circulations and perfusions, aggregatedplatelets tend to block the blood vessels and portions of thecirculation apparatus. This blocking is avoided by the presence of thesecompounds. For this purpose, the compound is added gradually or insingle or multiple portions to the circulating blood, to the blood ofthe donor animal, to the perfused body portion, attached or detached, tothe recipient, or to two or all of those at a total steady state dose ofabout 0.001 to 10 mg. per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals, e.g., cats, dogs,rabbits, monkeys, and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplants.

The prostaglandins so cited above as useful in place of oxytocin toinduce labor are used in pregnant female animals, including man, cows,sheep, and pigs, at or near term, or in pregnant animals withintrauterine death of the fetus from about 20 weeks to term. For thispurpose, the compound is infused intravenously at a dose of 0.01 to 50μg. per kg. of body weight per minute until or near the termination ofthe second stage of labor, i.e., expulsion of the fetus. These compoundsare especially useful when the female is one or more weeks post-matureand natural labor has not started, or 12 to 60 hours after the membraneshave ruptured and natural labor has not yet started. An alternativeroute of administration is oral.

These compounds are further useful for controlling the reproductivecycle in menstruating female mammals, including humans. By the termmenstruating female mammals is meant animals which are mature enough tomenstruate, but not so old that regular menstruation has ceased. Forthat purpose the prostaglandin is administered systemically at a doselevel in the range 0.01 to about 20 mg. per kg. of body weight of thefemale mammal, advantageously during a span of time startingapproximately at the time of ovulation and ending approximately at thetime of menses or just prior to menses. Intravaginal and intrauterineroutes are alternate methods of administration. Additionally, expulsionof an embryo or a fetus is accomplished by similar administration of thecompound during the first or second trimester of the normal mammaliangestation period.

These compounds are further useful in causing cervical dilation inpregnant and nonpregnant female mammals for purposes of gynecology andobstetrics. In labor induction and in clinical abortion produced bythese compounds, cervical dilation is also observed. In cases ofinfertility, cervical dilation produced by these compounds is useful inassisting sperm movement to the uterus. Cervical dilation byprostaglandins is also useful in operative gynecology such as D and C(Cervical Dilation and Uterine Curettage) where mechanical dilation maycause perforation of the uterus, cervical tears, or infections. It isalso useful in diagnostic procedures where dilation is necessary fortissue examination. For these purposes, the prostaglandin isadministered locally or systemically.

The prostaglandin, for example, is administered orally or vaginally atdoses of about 5 to 50 mg. per treatment of an adult female human, withfrom one to five treatments per 24 hour period. Alternatively theprostaglandin is administered intramuscularly or subcutaneously at dosesof about one to 25 mg. per treatment. The exact dosages for thesepurposes depend on the age, weight, and condition of the patient oranimal.

These compounds are further useful in domestic animals as anabortifacient (especially for feedlot heifers), as an aid to estrusdetection, and for regulation or synchronization of estrus. Domesticanimals include horses, cattle, sheep, and swine. The regulation orsynchronization of estrus allows for more efficient management of bothconception and labor by enabling the herdsman to breed all his femalesin short pre-defined intervals. This synchronization results in a higherpercentage of live births than the percentage achieved by naturalcontrol. The prostaglandin is injected or applied in a feed at doses of0.1-100 mg. per animal and may be combined with other agents such assteroids. Dosing schedules will depend on the species treated. Forexample, mares are given the prostaglandin 5 to 8 days after ovulationand return to estrus. Cattle, are treated at regular intervals over a 3week period to advantageously bring all into estrus at the same time.

The PGA compounds and derivatives and salts thereof increase the flow ofblood in the mammalian kidney, thereby increasing volume and electrolytecontent of the urine. For that reason, PGA compounds are useful inmanaging cases of renal dysfunction, especially those involving blockageof the renal vascular bed. Illustratively, the PGA compounds are usefulto alleviate and correct cases of edema resulting, for example, frommassive surface burns, and in the management of shock. For thesepurposes, the PGA compounds are preferably first administered byintravenous injections at a dose in the range 10 to 1000 μg. per kg. ofbody weight or by intravenous infusion at a dose in the range 0.1 to 20μg. per kg. of body weight per minute until the desired effect isobtained. Subsequent doses are given by intravenous, intramuscular, orsubcutaneous injection or infusion in the range 0.05 to 2 mg. per kg. ofbody weight per day.

The compounds so cited above as promoters and acceleraters of growth ofepidermal cells and keratin are useful in animals, including humans,useful domestic animals, pets, zoological specimens, and laboratoryanimals for this purpose. For this reason, these compounds are useful topromote and accelerate healing of skin which has been damaged, forexample, by burns, wounds, and abrasions, and after surgery. Thesecompounds are also useful to promote and accelerate adherence and growthof skin autografts, especially small, deep (Davis) grafts which areintended to cover skinless areas by subsequent outward growth ratherthan initially, and to retard rejection of homografts.

For the above purposes, these compounds are preferably administeredtopically at or near the site where cell growth and keratin formation isdesired, advantageously as an aerosol liquid or micronized powder spray,as an isotonic aqueous solution in the case of wet dressings, or as alotion, cream, or ointment in combination with the usualpharmaceutically acceptable diluents. In some instances, for example,when there is substantial fluid loss as in the case of extensive burnsor skin loss due to other causes, systemic administration inadvantageous, for example, by intravenous injection or infusion,separate or in combination with the usual infusions of blood, plasma, orsubstitutes thereof. Alternative routes of administration aresubcutaneous or intramuscular near the site, oral, sublingual, buccal,rectal, or vaginal. The exact dose depends on such factors as the routeof administration, and the age, weight, and condition of the subject. Toillustrate, a wet dressing for topical application to second and/orthird degree burns of skin area 5 to 25 square centimeters wouldadvantageously involve use of an isotonic aqueous solution containing 1to 500 μg. per ml. of the prostaglandin pound. Especially for topicaluse, these prostaglandins are useful in combination with antibiotics,for example, gentamycin, neomycin, polymixin, bacitracin, spectinomycin,and oxytetracycline, with other antibacterials, for example, mafenidehydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone, andwith corticoid steroids, for example, hydrocortisone, prednisolone,methylprednisolone, and fluprednisolone, each of those being used in thecombination at the usual concentration suitable for its use alone.

In addition to the discovery of the prostaglandins cited above, variousprostaglandin analogs have likewise been discovered. In particular,there are known prostaglandin analogs of the formula ##STR22## wherein Dis ##STR23## wherein R₈ is hydrogen or hydroxy;

wherein L₁ is ##STR24## or a mixture of ##STR25## and ##STR26## whereinR₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different,with the proviso that one of R₃ and R₄ is fluoro, only when the other ishydrogen or fluoro;

wherein M₁ is ##STR27## or ##STR28## wherein R₅ is hydrogen or methyl;wherein R₇ is --(CH₂)_(m) --CH₃, wherein m is one to 5, inclusive,cis--CH═CH--CH₂ --CH₃, or ##STR29## wherein T is chloro, fluoro,trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy ofone to 3 carbon atoms, inclusive, the various T's being the same ordifferent, s is zero, one, 2, or 3, and Z₃ is oxa or methylene, with theproviso that not more than two T's are other than alkyl, and the furtherproviso that Z₃ is oxa only when R₃ and R₄ are hydrogen or methyl, beingthe same or different;

wherein Y₁ is trans--CH═CH--, --CH₂ CH₂ --, cis--CH═CH--, or--C.tbd.C--; and

wherein Z₁ is

    cis--CH═CH--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 --, (1)

    cis--CH═CH--CH.sub.2 --(CH.sub.2).sub.g --CF.sub.2 --, (2)

    cis--CH.sub.2 --CH═CH--(CH.sub.2).sub.g --CH.sub.2 --, (3)

    --(ch.sub.2).sub.3 --(ch.sub.2).sub.g --CH.sub.2 --,       (4)

    --(ch.sub.2).sub.3 --(ch.sub.2).sub.g --CF.sub.2 --,       (5)

    --ch.sub.2 --o--ch.sub.2 --(ch.sub.2).sub.g --CH.sub.2 --, (6) ##STR30## wherein g is one, 2, or 3.

While the use and preparation of many of the prostaglandin analogsdescribed above is widely known in the art, the Appendix, heretoprovides a discussion of the preparation of each of the variouscompounds depicted by formula I above.

For the prostaglandin analogs described in formula I above, a convenientclassification system according to cyclopentane ring structure iseffected by referencing:

a. PGF.sub.α -type compounds when D is ##STR31##

b. 11-deoxy-PGF.sub.α -type compounds when D is ##STR32##

c. PGE-type compounds when D is ##STR33##

d. 11-deoxy-PGE-type compounds when D is ##STR34##

e. PGF.sub.β -type compounds when D is ##STR35##

f. PGD-type or 9β-PGD-type compounds when D is ##STR36## and

g. 9-deoxy-PGD-type compounds when D is ##STR37##

h. 9-deoxy-9,10-didehydro-PGD-type compounds when D is ##STR38## and

i. PGA-type compounds when D is ##STR39##

j. PGB-type compounds when D is ##STR40##

k. 8β,12α-PGF.sub.α -type compounds when D is ##STR41##

l. 8β,12α-11-deoxy-PGF.sub.α -type compounds when D is ##STR42##

m. 8β,12α-PGE-type compounds when D is ##STR43##

n. 8β,12α-11-deoxy-PGE-type compounds when D is ##STR44##

o. 8β,12α-PGF.sub.β -type compounds when D is ##STR45##

p. 8β,12α-PGD-type or 8β,9β,12α-PGD-type compounds when D is ##STR46##

q. 8β,12α-9-deoxy-PGD-type compounds when D is ##STR47## and

s. 8β,12α-PGA-type compounds when D is ##STR48##

Those prostaglandin analogs wherein Z₁ is cis--CH═CH--CH₂ --(CH₂)_(g)--CH₂ -- or cis--CH═CH--CH₂ --(CH₂)_(g) --CF₂ -- are named as "PG₂ "compounds. The latter compounds are further characterized as"2,2-difluoro" PG₂ -type compounds. When g is 2 or 3, the prostaglandinanalogs so described are "2a-homo" or "2a,2b-dihomo" compounds, since inthis event the carboxy terminated side chain contains 8 or 9 carbonatoms, respectively, in place of the 7 carbon atoms contained in PGE₁.These additional carbon atoms are considered as though they wereinserted between the C-2 and C-3 positions. Accordingly, theseadditional carbon atoms are referred to as C-2a and C-2b, counting fromthe C-2 to the C-3 position.

Further when Z₁ is --(CH₂)₃ --(CH₂)_(g) --CH₂ -- or --(CH₂)₃ --(CH₂)_(g)--CF₂, wherein g is as defined above, the PG analogs so described are"PG₁ " compounds. When g is 2 or 3, the "2a-homo" and "2a, 2b-dihomo"compounds are described as is discussed in the preceding paragraph.

When Z₁ is --CH₂ 13 0--CH₂ --(CH₂)_(g) --CH₂ -- the PG analogs sodescribed are named as "5-oxa-PG₁ " compounds. When g is 2 or 3, thecompounds so described are "2a-homo" or "2a, 2b-dihomo" compounds,respectively, as discussed above.

When Z₁ is cis--CH₂ --CH═CH--(CH₂)_(g) --CH₂ --, wherein g is as definedabove, the PG analogs so described are named "cis-4,5-didehydro-PG₁ "compounds. When g is 2 or 3, the compounds so described are furthercharacterized as "2a-homo" or "2a,2b-dihomo" compounds, respectively, asdiscussed above.

For the PG analogs wherein Z₁ is ##STR49## there are described,respectively, 3-oxa-3,7-inter-m-phenylene-4,5,6-trinor or3,7-inter-m-phenylene-4,5,6-trinor-PG-type compounds, when g is one.When g is 2 or 3, the above compounds are additionally described as"2a-homo" or "2a,2b-dihomo" PG-type compounds, respectively.

The prostaglandin analogs described herein which contain a cis--CH═CH--moiety at the C-13 to C-14, the compounds so described are "13-cis"compounds.

Further when the C-13 to C-14 moiety is --C.tbd.C-- or --CH₂ CH₂ -- thecompounds so described are named as "13,14-didehydro" or "13,14-dihydro"compounds, respectively.

When R₇ is --(CH₂)_(m) --CH₃, wherein m is as defined above, the PGanalogs so described are named as "19,20-dinor", "20-nor", "20-methyl",or "20-ethyl" compounds when m is one, 2,4, or 5, respectively. When R₇is ##STR50## wherein T and s are as defined above, the PG analogs sodescribed are named as "17-phenyl-18,19,20-trinor" compounds, when s is0. When s is one, 2, or 3, the corresponding compounds are named as"17-(substituted phenyl)-18,19,20-trinor" compounds.

When R₇ is ##STR51## wherein T and s are as defined above, and neitherR₃ nor R₄ is methyl, the PG analogs so described are named as"16-phenoxy-17,18,19,20-tetranor" compounds, when s is zero. When s isone, 2, or 3, the corresponding compounds are named as "16-(substitutedphenoxy)-17,18,19,20-tetranor" compounds. When one and only one of R₃and R₄ is methyl or both R₃ and R₄ are methyl, then the correspondingcompounds wherein R₇ is as defined in this paragraph are named as"16-phenoxy or 16-(substituted phenoxy)-18,19,20-trinor" compounds or"16-methyl-16-phenoxy or 16-(substituted phenoxy)-18,19,20-trinor"compounds, respectively.

When R₇ is cis--CH═CH--CH₂ --CH₃, the compounds so described are "PG₃ "or "cis-17,18-didehydro" compounds depending on whether Z₁ iscis--CH═CH--(CH₂)_(g) --C(R₂)₂, wherein R₂ is hydrogen or fluoro, oranother moiety, respectively.

When at least one of R₃ and R₄ is not hydrogen then (except for the16-phenoxy compounds discussed above) there are described the"16-methyl" (one and only one of R₃ and R₄ is methyl), "16,16-dimethyl"(R₃ and R₄ are both methyl), "16-fluoro" (one and only one of R₃ and R₄is fluoro), "16,16-difluoro" (R₃ and R₄ are both fluoro) compounds. Forthose compounds wherein R₃ and R₄ are different, the prostaglandinanalogs so represented contain an asymmetric carbon atom at C-16.Accordingly, two epimeric configurations are possible: "(16S)" and"(16R)". Further, there is described by this invention the C-16 epimericmixture: "(16RS)".

When R₅ is methyl, the compounds so described are named as "15-methyl"compounds.

Some formulas of 13-cis-cyclopentane derivatives described hereinaftercontain a moiety of the formula: ##STR52## wherein the cyclopentane ringis variously substituted, wherein M is variously defined according tothe subscripts provided herein; wherein L₁ and R₇ are as defined above;and wherein Y₄ is cis--CH═CH--. Optionally the above formula is depictedwith one or both of L₁ and M above the carbon atom to which it isattached, e.g., as follows: ##STR53## When either of the aboverepresentations is employed, it is hereby defined to indicate thefollowing convention with respect to the representation of the cis-13double bond: ##STR54## Further in employing this convention when M is,for example, ##STR55## or ##STR56## then the correspondingrepresentations: ##STR57## or ##STR58## are intended, respectively.Accordingly all the formulas herein which represent 13-cis cyclopentanederivatives are depicted by the same convention as that for thecis-13-PGE₁ when drawn as follows: ##STR59## Thus, by this conventionthe (15S)-hydroxy of cis-13-PGE₁ is in the beta configuration.

cis-13-PG-type compounds as drawn herein which have an hydroxy ormethoxy at C-15 in the alpha configuration are of the opposite relativestereochemical configuration at C-15 as that of cis-13-PGE₁, and aretherefore named as "15-epi" compounds. When the beta hydroxy or methoxyconfiguration is present, no special designation of this stereochemistryis provided.

Accordingly, 15-epi-16,16-difluoro-cis-13-PGD₂ is depicted herein asfollows: ##STR60##

Alternate representations of cis-13-PGE₁ affect the depiction of C-15 asan alpha or beta hydroxy. Thus, by a representation contrary to theinstant convention, cis-13-PGE₁ appears as follows: ##STR61##

Accordingly, care must be taken to consistently draw the formulas ofcis-13-PG-type compounds herein such that the C-15 carbon atoms isproperly represented, i.e., all cis-13-15-epi-PG's are of the15α-hydroxy configuration.

13,14-trans-13,14-dihydro, or 13,14-didehydro cyclopentane derivativeswhich contain the moiety ##STR62## wherein the cyclopentane ring isvariously substituted, wherein M is variously defined according to thesubscripts provided herein; wherein L₁ and R₇ are as defined above; andwherein Y₃ is trans--CH═CH--, --CH₂ CH₂ --, or --C.tbd.C-- respectively.When this representation is employed, it is hereby defined to indicatethe following convention with respect to the representation of the C-13to C-14 moiety: ##STR63## or ##STR64## respectively. Likewise inemploying this convention when M is, for example ##STR65## or ##STR66##then the corresponding representation for the trans-13 compounds:##STR67## or ##STR68## the 13,14-dihydro compounds: ##STR69## or##STR70## and the 13,14-didehydro compounds: ##STR71## or ##STR72## areintended, respectively. Accordingly all the formulas herein whichrepresent trans-13, 13,14-dihydro, or 13,14-didehydro-cyclopentanederivatives are depicted by the same convention as that for PGE₁ whendrawn as above, i.e., ##STR73##

Thus, for all trans-13, 13,14-dihydro, or 13,14-didehydro-PG-typecompounds, as drawn herein the 15α-hydroxy configuration corresponds tothe relative C-15 stereochemical configuration of PGE₁ as obtained frommammalian tissues. No special designation of the C-15 stereochemistry isprovided in naming these compounds. For compounds of the oppositestereochemical configuration at C-15 (i.e., 15β-hydroxy), thedescription "15-epi" will be employed.

The prostaglandin analogs of formula I are known to correspond to theprostaglandins described above, in that these prostaglandin analogsexhibit prostaglandin-like activity.

Specifically the PGE-, 8β,12α-PGE-, 8β,12α-11-deoxy-PGE-, and11-deoxy-PGE-type compounds correspond to the PGE compounds describedabove, in that these PGE-, 8β,12α-PGE-, 8β,12α-11-deoxy-PGE-, and11-deoxy-PGE-type compounds are useful for each of the above-describedpurposes for which the PGE compounds are used, and are used in the samemanner as the PGE compounds, as described above.

The PGF.sub.α -, 8β,12α-PGF.sub.α -, 8β,12α-11-deoxy-PGF.sub.α -, and11-deoxy-PGF.sub.α -type compounds correspond to the PGF.sub.α compoundsdescribed above, in that these PGF.sub.α -, 8β,12α-PGF.sub.α -,8β,12α-11-deoxy-PGF.sub.α -, and 11-deoxy-PGF.sub.α -type compounds areuseful for each of the above-described purposes for which the PGF.sub.αcompounds are used, and are used in the same manner as the PGFcompounds, as described above.

The PGD-, 9β-PGD-, 8β,12α-PGD-, 8β,9β,12α-PGD-, 9-deoxy-PGD-,8β,12α-9-deoxy-PGD-, 8β,12α-9,10-didehydro-9-deoxy-PGD-, and9,10-didehydro-9-deoxy-PGD-type compounds of formula I correspond to thePGE or PGF.sub.α compounds described above, in that these PGD-,8β,12α-PGD-, 9-deoxy-PGD-, 8β,12α-9-deoxy-PGD-,8β,12α-9-deoxy-9,10-didehydro-PGD-, or 9-deoxy-9,10-didehydro-PGD-typecompounds are useful for each of the above-described purposes for whicheither the PGE or PGF.sub.α compounds are used, and are used in the samemanner as the PGE and PGF.sub.α compounds, as described above.

The PGA- or 8β,12α-PGA-type compounds of formula I correspond to the PGAcompounds described above, in that these PGA- or 8β,12α-PGA-typecompounds are useful for each of the above described purposes for whichthe PGA compounds are used, and are used in the same manner as the PGAcompounds, as described above. The PGB-type compounds of formula Icorrespond to the PGB compounds described above in that the PGBcompounds are useful for each of the above described purposes for whichPGB compounds are used, and are used in the same manner as the PGBcompounds described above.

The prostaglandins described above, ar all known to be potent in causingmultiple biological responses even at low doses. Moreover, for manyapplications, there prostaglandins are known to exhibit a relativelyshort duration of biological activity. Significantly, the prostaglandinanalogs of formula I are known to be substantially more selective withregard to potency in causing prostaglandin-like biological responses,and have a somewhat longer duration of biological activity. Thus, eachof these prostaglandin analogs is known to be equally or even moreuseful than one of the corresponding prostaglandins described above forat least one of the pharmacological purposes indicated above for thelatter.

Another property of the prostaglandin analogs of formula I, comparedwith the corresponding prostaglandins, is that these PG analogs areknown to be capable of effective administration orally, sublingually,intravaginally, buccally, or rectally in many cases where thecorresponding prostaglandin is known to be effective only by theintravenous, intramuscular, or subcutaneous injection or infusionmethods of administration indicated above as used of theseprostaglandins. When alternate routes of administration are employed,they are known to facilitate maintaining unilevels of these compounds inthe body with fewer, shorter, or smaller doses, and to make possibleself-administration by the patient.

Accordingly, the prostaglandin analogs of formula I are known to becapable of administration in various ways for various purposes: e.g.,intravenously, intramuscularly, subcutaneously, orally, intravaginally,rectally, buccally, sublingually, topically, and in the form of sterileimplants for prolonged action. For intravenous injection or infusion,sterile aqueous isotonic solutions are known to be preferred. Forsubcutaneous or intramuscular injection, sterile solutions orsuspensions are used. Tablets, capsules, and liquid preparations such assyrups, elixirs, and simple solutions, with the usual pharmaceuticalcarriers are used for oral sublingual administration. For rectal orvaginal administration, suppositories prepared as known in the art areused. For tissue implants, the use of sterile tablets or silicone rubbercapsules or other objects containing or impregnated with the substanceis known.

Methods for the preparation of large ringed lactones are known in theart. See, for example, E. J. Corey, et al., Journal of the AmericanChemical Society 96: 5614 (1974). Further, certain 1,9 lactones ofcyclopentane containing carboxylic acids are known in the art. SeeSourth African Application No. 737,357, Derwent Farmdoc CPI No. 28414V,which discloses 1,9-lactones of ω-heterocyclic prostaglandin analogs;Japanese Application No. 50-0037-793, Derwent Farmdoc CPI No. 61147W,which discloses 15-deoxy-15-methyl-PGF₂α, 1,9-lactone; and E. J. Corey,et al., Journal of the American Chemical Society 97: 653 (1975), whichdiscloses PGF₂α 1,9-lactone. Further, the latter reference additionallydiscloses PGF₂α, 1,15-lactone.

Finally, see Japanese Patent Application No. 50013-385, Derwent FarmdocCPI No. 56267W, which discloses 1,9-lactones of PGF₂α and(15RS)-15-methyl-PGF₂α.

SUMMARY OF THE INVENTION

This invention provides novel bicyclic, cyclopentane-containinglactones.

This invention further provides novel processes for preparing theselactones.

In particular, this specification discloses:

1. a 1,9-, 1,11-, or 1,15-lactone of a prostaglandin analog of theformula ##STR74## or ##STR75## wherein L₁, M₁, R₇, Y₁, and Z₁ are asdefined above;

2. a 1,9- or 1,15-lactone of a prostaglandin analog of the formula##STR76## or ##STR77## wherein L₁, M₁, R₇, Y₁, and Z₁ are as definedabove;

and

wherein W₂ is ##STR78##

3. a 1,11 or 1,15-lactone of a prostaglandin analog of the formula##STR79## or ##STR80## wherein L₁, M₁, R₇, Y₁, and Z₁ are as definedabove;

4. a 1,15-lactone of a prostaglandin analog of the ##STR81## wherein L₁,M₁, R₇, Y₁, and Z₁ are as defined above.

The charts herein describe methods whereby the prostaglandins orprostaglandin analogs, hereinabove described, are transformed to 1,9-,1,11-, or 1,15-lactones. Since each of these prostaglandins orprostaglandin analogs exhibits an hydroxyl at C-15, each is thereforecapable of forming a 1,15-lactone. Further, 1,9- or 1,11-lactones ofeach of the prostaglandins or prostaglandin analogs hereinabovedescribed is likewise capable of formation, depending upon whether thecyclopentane ring structure exhibits a 9-hydroxyl or an 11-hydroxyl,respectively. Thus, the PGA-, PGB-, 9-deoxy-PGD-,9-deoxy-9,10-didehydro-PGD-, and 11-deoxy-PGE-type compounds or their8β,12α-isomers are capable of forming only 1,15-lactones. The PGD-,9β-PGD-, 11-deoxy-PGF.sub.α -, and 11-deoxy-PGF.sub.β -type compounds ortheir 8β,12α-isomers are capable only of forming 1,9- or 1,15-lactones.The PGE-type compounds or their 8β,12α-isomers are capable of formingonly 1,11- or 1,15-lactones. Finally, the PGF.sub.α - or PGF.sub.β -typecompounds or their 8β,12α-isomers are capable of forming 1,9-, 1,11-, or1,15-lactones. ##STR82##

Whereas the present specification describes each of the various lactonesof each of the various prostaglandins or prostaglandin analogs describedabove, the charts below describe methods whereby the desired lactoneproduct is obtained with high selectivity. In each case, thelactonization step itself proceeds by methods known in the art.

For example, South African Pat. No. 737,357 (Derwent Farmdoc CPI No.28,414V) teaches the preparation of 1,9-lactones of certain PG-typecompounds by application of heat to neat samples of the PG-type product.However, for the purposes of the present invention, the method describedtherein is unsuitable in that only complex mixtures of products arethereby produced.

A further method for lactonization of PG-type compounds is described byJapanese Patent Application No. 5-0037-793 (Derwent Farmdoc CPl No.61147W) and Japanese Patent Application No. 5-0013-385 (Derwent FarmdocCPl No. 56267W) wherein trifluoroacetic acid and trifluoroaceticanhydride are employed as lactonization agents. Further, lactonizationfor prostaglandin-type products is accomplished by the lactonizationprocedure of S. Masaume, Journal of the American Chemical Society 97,3515 (1975). By this procedure a mercuric trifluoroacetate catalyzedring closure of an ω-hydroxy-t-butythiol ester is employed.

However, the preferred procedure of lactonization of the prostaglandinanalog described herein proceeds by transformation of the carboxyl ofthe prostaglandin type compound to a corresponding 2-pyridinethiolester, followed by ring closure. The general method for this preferredlactonization process is described by E. J. Corey, Journal of theAmerican Chemical Society 96, 5614 (1974), and its application to PGF₂αis described by E. J. Corey, et al., Journal of the American ChemicalSociety 97, 653 (1975). By this preferred procedure the formation of the2-pyridinethiol ester proceeds by reaction of the prostaglandin typefree acid with 1.5 equivalents of 2,2'-dipyridyl disulfide and 1.5equivalents of triphenylphosphine in a dry (anhydrous) oxygen freexylene or benzene diluent. The 2-pyridinethiol esterification proceedsat room temperature, in about 2-24 hr. The ring closure then proceeds byfirst diluting the thiol ester obtained above with dry, oxygen freexylene or benzene and thereafter heating to reflux for 1-24 hr.

A modification of the preferred procedure for lactonization is describedby H. Gerlach, et al., Helv. Chim. Acta. 57 (8) 2661 (1974). Thismodification involves ring closure of an ω-hydroxy-2-pyridine thiolester with silver ion (perchlorate or fluoroborate) catalysis in benzeneat room temperature.

With respect to the charts below:

L₁, m₁, y₁, and R₇ are as defined above.

R₈ is hydrogen or hydroxy.

R₉ is an acyl protecting group.

R₁₀ is a blocking group.

R₃₃ is --O--Si--(G₁)₃ wherein G₁ is alkyl, cycloalkyl, aralkyl, phenyl,or phenyl substituted with alkyl or halogen, the various G₁ 's of a--Si--(G₁)₃ moiety being the same or different.

Z₄ is ##STR83## wherein T and s are as defined above, and

wherein h is 2 to 4, inclusive, preferably 3.

M₇ is ##STR84## or ##STR85##

M₈ is ##STR86## or ##STR87## wherein R₅ and R₁₀ are as defined above.M₁₁ is ##STR88## or ##STR89##

M₁₅ is ##STR90## or ##STR91##

M₁₆ is ##STR92## or ##STR93##

M₁₈ is ##STR94## or ##STR95##

Acyl protecting groups, according to R₉, include:

a. benzoyl;

b. benzoyl substituted with one, 2, 3, 4, or 5 alkyl of one to 4 carbonatoms, inclusive, phenyl alkyl of 7 to 10 carbon atoms, inclusive,phenyl, or nitro, with the proviso that not more than 2 substituents areother than alkyl, and that the total number of carbon atoms in thesubstituents does not exceed 10 carbon atoms, with the further provisothat the substituents may be the same or different;

c. benzoyl substituted with alkoxy carbonyl wherein the alkoxy carbonylmoiety is of 2 to 5 carbon atoms, inclusive;

d. naphthoyl;

e. naphthoyl substituted with one to 9, inclusive, alkyl of one to 4carbon atoms, inclusive, phenyl alkyl of 7 to 10 carbon atoms,inclusive, or nitro, with the proviso that not more than 2 substituentson either of the naphthyl rings does not exceed 10 carbon atoms, withthe further proviso that the various substituents are the same ordifferent; or

f. alkanoyl of 2 to 12 carbon atoms, inclusive.

In preparing these acyl derivatives of the hydroxy-containing compoundsherein methods generally known in the art are employed. Thus, forexample, an aromatic acid of the formula R₉ OH, wherein R₉ is as definedabove (e.g., benzoic acid), is reacted with the hydroxy-containingcompound in the presence of a dehydrating agent, e.g. sulfuric acid,zinc chloride, or phosphoryl chloride; or alternatively an anhydride ofthe aromatic acid of the formula (R₉)₂ O (e.g., benzoic anhydride) isused.

Preferably, however, the process described in the above paragraphproceeds by use of the appropriate acyl halide, e.g., R₉ Hal, whereinHal is chloro, bromo, or iodo. For example, benzoyl chloride is reactedwith the hydroxy-containing compound in the presence of a hydrogenchloride scavenger, e.g. a tertiary amine such as pyridine,triethylamine, or the like. The reaction is carried out under a varietyof conditions, using procedures generally known in the art. Generallymild conditions are employed: 20°-60° C., contacting the reactants in aliquid medium (e.g., excess pyridine or an inert solvent such asbenzene, toluene, or chloroform). The acylating agent is used either instoichiometric amount or in substantial stoichiometric excess.

As examples of R₉, the following compounds are available as acids (R₉OH), anhydrides (R₉)₂ O, or acyl chlorides (R₉ Cl): benzoyl; substitutedbenzoyl, e.g., p-phenylbenzoyl, (2-, 3-, or 4-)-methylbenzoyl, (2-, 3-,or 4-)-ethylbenzoyl, (2-, 3-, or 4-)-isopropylbenzoyl, (2-, 3-, or4-)-tert-butylbenzoyl, 2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl,2-isopropyltoluyl, 2,4,5-trimethylbenzoyl, pentamethylbenzoyl,alpha-phenyl(2-, 3-, or 4-)-toluyl, (2-, 3-, or 4-)-phenethylbenzoyl,(2-, 3-, or 4-)-nitrobenzoyl, (2,4-, 2,5-, or 2,3-)-dinitrobenzoyl,2,3-dimethyl-2-nitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl,2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethylbenzoyl,2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethylbenzoyl; mono esterifiedphthaloyl, isophthaloyl, or terephthaloyl; 1- or 2-naphthoyl;substituted naphthoyl, e.g., (2-, 3-, 4-, 5-, 6-, or7-)-methyl-1-naphthoyl, (2- or 4 -) ethyl-1-naphthoyl,2-isopropyl-1-naphthoyl, 4,5-dimethyl-1-naphthoyl,6-isopropyl-4-methyl-1-naphthoyl, 8-benzyl-1-naphthoyl, (3-, 4-, 5-, or8-)-nitro-1-naphthoyl, 4,5-dinitro-1-naphthoyl, (3-, 4-, 6-, 7-, or8-)methyl-1-naphthoyl, 4-ethyl-2-naphthoyl, and (5- or8-)nitro-2-naphthoyl; and acetyl.

There may be employed, therefore, benzoyl chloride, 4-nitrobenzoylchloride, 3,5-dinitrobenzoyl chloride, or the like, i.e. R₉ Cl compoundscorresponding to the above R₉ groups. If the acyl chloride is notavailable, it is prepared from the corresponding acid and phosphoruspentachloride as is known in the art. It is preferred that the R₉ OH,(R₉)₂ O, or R₉ Cl reactant does not have bulky hindering substituents,e.g. tert-butyl on both of the ring carbon atoms adjacent to thecarbonyl attaching site.

The acyl protecting groups, according to R₉, are removed by deacylation.Alkali metal carbonates are employed effectively at ambient temperaturefor this purpose. For example, potassium carbonate in methanol at about25° C. is advantageously employed. By the preferred process herein,however, an alkali metal hydroxide is employed in aqueous methanol, e.g.potassium hydroxide.

Those blocking groups within the scope of R₁₀ are any group whichreplaces a hydroxy hydrogen and is neither attacked by nor as reactiveto the reagents used in the transformations used herein as an hydroxy isand which is subsequently replaceable with hydrogen in the preparationof the prostaglandin-type compounds. Several blocking groups are knownin the art, e.g. tetrahydropyranyl and substituted tetrahydropyranyl.See for reference E. J. Corey, Proceedings of the Robert A. WelchFoundation Conferences on Chemical Research, 12, Organic Synthesis, pgs.51-79 (1969). Those blocking groups which have been found usefulinclude:

a. tetrahydropyranyl;

b. tetrahydrofuranyl; and

c. a group of the formula

    --C(OR.sub.11)(R.sub.12)--CH(R.sub.13)(R.sub.14),

wherein R₁₁ is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms,inclusive, phenyl or phenyl substituted with one to 3 alkyl of one to 4carbon atoms, inclusive, wherein R₁₂ and R₁₃ are alkyl of one to 4carbon atoms, inclusive, phenyl, phenyl substituted with one, 2, or 3alkyl of one to 4 carbon atoms, inclusive, or when R₁₂ and R₁₃ are takentogether --(CH₂)_(a) -- or --(CH₂)_(b) -- O --(CH₂)_(c) wherein a is 3,4, or 5, or b is one, 2, or 3, and c is one, 2, or 3, with the provisothat b plus c is 2, 3, or 4, with the further proviso that R₁₂ and R₁₃may be the same or different, and wherein R₁₄ is hydrogen or phenyl.

When the blocking group R₁₀ is tetrahydropyranyl, the tetrahydropyranylether derivative of any hydroxy moieties of the PG-type intermediatesherein is obtained by reaction of the hydroxy-containing compound with2,3-dihydropyran in an inert solvent, e.g. dichloromethane, in thepresence of an acid condensing agent such as p-toluenesulfonic acid orpyridine hydrochloride. The dihydropyran is used in large stoichiometricexcess, preferably 4 to 100 times the stoichiometric amount. Thereaction is normally complete in less than an hour at 20° to 50° C.

When the blocking group is tetrahydrofuranyl, 2,3-dihydrofuran is used,as described in the preceding paragraph, in place of the2,3-dihydropyran.

When the blocking group is of the formula

    --C(OR.sub.11)(R.sub.12)--CH(R.sub.13)(R.sub.14),

wherein R₁₁, R₁₂ R₁₃, and R₁₄ are as defined above, the appropriatereagent is a vinyl ether, e.g. isobutyl vinyl ether or any vinyl etherof the formula

    C(OR.sub.11)(R.sub.12)═C(R.sub.13)(R.sub.14),

wherein R₁₁, R₁₂, R₁₃, and R₁₄ are as defined above; or an unsaturatedcyclic or heterocyclic compound, e.g. 1-cyclohexen-1-yl methyl ether, or5,6-dihydro-4-methoxy-2H-pyran. See C. B. Reese, et al., Journal of theChemical Society 89, 3366 (1967). The reaction conditions for such vinylethers and unsaturated compounds are similar to those for dihydropyranabove.

The blocking groups according to R₁₀ are removed by mild acidichydrolysis. For example, by reaction with (1) hydrochloric acid inmethanol; (2) a mixture of acetic acid, water, and tetrahydrofuran, or(3) aqueous citric acid or aqueous phosphoric acid in tetrahydrofuran,at temperatures below 55° C., hydrolysis of the blocking groups isachieved.

Various reactions in the succeeding charts introduce silyl groups of theformula --Si(G₁)₃. In some cases, such silylations are general, in thatthey silylate all hydroxy hydrogens, while in other cases they areselective, in that while one or more hydroxyls are silylated, at leastone other hydroxyl remains unaffected. For any of these silylations,silyl groups within the scope of --Si(G₁)₃ include trimethylsilyl,dimethylphenylsilyl, triphenylsilyl, t-butyldimethylsilyl, ormethylphenylbenzylsilyl. With regard to G₁, examples of alkyl aremethyl, ethyl, propyl, isobutyl, butyl, sec-butyl, tert-butyl, pentyl,and the like. Examples of aralkyl are benzyl, phenethyl, α-phenylethyl,3-phenylpropyl, α-naphthylmethyl, and 2-(β-naphthyl)ethyl. Examples ofphenyl substituted with halo or alkyl are p-chlorophenyl,m-fluorophenyl, o-tolyl, 2,4-dichlorophenyl, p-tert-butylphenyl,4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.

These silyl groups are known in the art. See for example, Pierce"Silylation of Organic Compounds," Pierce Chemical Company, Rockford,Ill. (1968). When silylated products of the charts below are intended tobe subject to chromatographic purification, then the use of silyl groupsknown to be unstable to chromatography (e.g. trimethylsilyl) should beavoided. Further, when silyl groups are to be introduced selectively,silylating agents which are readily available and known to be useful inselective silylations are employed. For example, triphenylsilyl groupsand t-butyldimethylsilyl groups are employed when selective introductionis required. Further, when silyl groups are to be selectively hydrolyzedover protecting groups according to R₁₀ or acyl protecting groups, thenthe use of silyl groups which are readily available and known to beeasily hydrolyzable with tetran-butylammonium fluoride are employed. Aparticularly useful silyl group for this purpose ist-butyldimethylsilyl, although other silyl groups (e.g. trimethylsilyl)are likewise employed.

With respect to Chart A, a method is provided where the formula XXIPGF.sub.α -, 11-deoxy-PGF.sub.α -, PFG.sub.β -, or 11-deoxyPGF.sub.β-type compound is transformed to a formula XXII 1,9-lactone or formulaXXV 1,15-lactone. Further, Chart A provides a method whereby the formulaXXIII 8β,12α-PGF.sub.α -, 11-deoxy-8β,12α-PGF.sub.α -, 8β,12α-PGF.sub.β-, or 11-deoxy-8β,12α-PGF.sub.β -type compound is transformed to acorresponding formula XXIV 1,9 or formula XXVI 1,15-lactone.

The lactonization of Chart A (XXI to XXII or XXV and XXIII to XXIV andXXVI) proceeds as is described above. The product of lactonization isrecovered as a mixture of 1,9- and 1,15-lactones. The predominantproduct is the 1,9-lactone, the proportion of which is increased by theuse of benzene rather than xylene, in the lactonization.

Chart B provides a method whereby the formula XXXVII PGD-type,1,9-lactone is prepared from the formula XXXI PGF.sub.α -type compound.Likewise, the 8β,12α-PGF.sub.α -type compound corresponding to formulaXXXI is employed to prepare a corresponding 8β,12α-PGD-type compoundcorresponding to formula XXXVII.

The formula XXXII compound is prepared from the formula XXXI compound bycyclo(alkyl or arylboronization). Accordingly, the bycicylic formulaXXXII compound is prepared by reaction of the formula XXXI compound witha slight stoichiometric excess of a corresponding alkyl or arylboronicacid. The course of the reaction is conveniently monitored gaschromatography and the reaction is preferably carried forth undervigorous stirring at reflux temperature. The preferred reaction diluentfor this transformation is methylene chloride, although other suitableorganic solvents are alternatively employed. The formula XXXII compoundso formed is then etherified at the C-15 position by replacing thehydroxyl hydrogen with a blocking group according to R₁₀. Proceduresdescribed above for the use of such blocking groups are employed.Thereafter the formula XXXIV compound is prepared from the formulaXXXIII compound by decycloboronization. For this purpose an alkalihydroxide (e.g. sodium, lithium, or potassium hydroxide) is combinedwith the formula XXXIII compound in a water miscible diluent capable ofyielding a homogeneous reaction mixture (e.g. methanol or ethanol). Theresulting solution is thereafter treated with dilute aqueous hydrogenperoxide. Thereafter the formula XXXV compound is prepared from theformula XXXIV compound by the lactonization procedure described above.This formula XXXV PGF.sub.α -type, 1,9-lactone is then transformed tothe corresponding PGD-type 1,9-lactone by oxidation of the C-11 hydroxyto an oxo. Methods known in the art for such an oxidation are employed.Thus, for example, a slight stoichiometric excess of Jones reagent isreacted with the formula XXXV compound at a temperature of -20° to -40°C. The formula XXXVII compound is then prepared from the formula XXXVIcompound by hydrolysis of the blocking group, employing methodshereinabove described.

Chart C provides a method whereby the formula XLI PGF.sub.α - or11-deoxy-PGF.sub.α -type compound is transformed to a formula XLVIIIPGF.sub.α -, 11-deoxy-PFG.sub.α -, or 11-deoxy-PGF.sub.β -type,1,15-lactone or a formula L PGE- or 11-deoxy-PGE-type, 1,15-lactone or aformula LII PGD-type, 1,15-lactone.

By the procedure of Chart C the formula XLI compound is transformed tothe formula XLII compound by selective silylation at C-11 and C-15 overC-9. Silyl groups according to the formula --Si(G₁)₃, wherein G₁ isdefined above, are advantageously employed. For selective monosilylationprocedures see U.S. Pat. No. 3,822,303, issued July 2, 1974, GermanOffenlegungsschrift No. 2,259,195 (Derwent Farmdoc CPI No. 36457U-B) orNetherlands Pat. No. 7,214,142 (Derwent Farmdoc CPI No. 26221U-B).Subsequently, there are performed the optional transformations of theformula XLII compound to the formula XLIII compound, and thereafter theformula XLIV compound. The formula XLIII compound is prepared from theformula XLII compound by oxidation of the 9-hydroxy to an oxo. Methodsknown in the art are employed. For example, the use of the Jones reagentor the Collins reagent or such additional reagents as are known totransform PGF.sub.α -type compounds to corresponding PGE-type compoundsis known and employed herein. Subsequently, the formula XLIII compoundis transformed to the formula XLIV compound by reduction of the 9-oxo ofthe formula XLIII compound to the corresponding 9-hydroxy compound andseparation of the 9β-hydroxy isomer from the isomeric mixture so formed.This reduction is performed by methods known in the art. For example,the use of sodium, potassium, or lithium borohydride reducing agents andsuch other agents as is known in the art for reduction of PGE-typecompounds to mixtures of PGF.sub.α and PGF.sub.β -type compounds isknown and employed herein. The 9-epimeric mixture is convenientlyseparated by silica gel chromatography, yielding the formula XLIVproduct.

Thereafter, the formula XLII or formula XLIV compounds are transformedto the formula XLV compound by replacing the 9-hydroxy hydrogen with ablocking group according to R₁₀. Methods known in the art andhereinabove described are employed. Thereafter the formula XLV compoundis transformed to the formula XLVI compound by selective hydrolysis ofany silyl groups over any blocking groups according to R₁₀. Thisselective removal of any silyl groups is accomplished by methods knownin the art. See for reference Corey, et al., Journal of the AmericanChemical Society 94, 6190 (1972). An especially useful reagent for thispurpose is tetra-n-butyl-ammonium fluoride in tetrahydrofuran.

Thereafter the formula XLVI compound is transformed to the formula XLVIIcompound by 1,15-lactonization. Lactonization methods described aboveare employed.

The formula XLVIII PGF.sub.α -, 11-deoxy-PGF.sub.α -, PGF.sub.β -, or11-deoxy-PGF.sub.β -type, 1,15-lactones are then prepared from theformula XLVII compound by hydrolysis of the blocking group according toR₁₀. This hydrolysis proceeds by methods hereinabove described.

The formula L PGE- or 11-deoxy-PGE-type, 1,15-lactone is then preparedfrom the formula XLVIII PGF.sub.α - or 11-deoxy-PGF.sub.α -type,1,15-lactone by first selective silylation at C-11 over C-9 (formulaXLIX) employing methods described in the transformation of the formulaXLI compound to the formula XLII compound; oxidizing the formula XLIXsilylated compounds so formed to a corresponding 9-oxo compound,employing methods known in the art for transformation of PGF.sub.α -typecompounds to PGE-type compounds as described above; and thereafteroptionally hydrolyzing any silyl group employing methods and proceduresknown in the art.

Alternatively the formula XLVII compound is employed in the preparationof the formula LI compound. In this transformation the 11-hydroxy of theformula XLVII compound is oxidized to the corresponding formula LI11-oxo compound. Procedures known in the art are employed. For example,see Tetrahedron Letters, 2235 (1974). Useful reagents for this purposeinclude those oxidizing reagents described above as useful in thetransformation of PGF-type compounds to PGE-type compounds. The formulaLI compound is then hydrolyzed at C-9, preparing the formula LIIPGD-type, 1,15-lactone.

Chart D provides a method whereby the formula LXI 8β,12α-PGF.sub.α -typecompound is transformed to a formula LXIV 8β,12α-PGF.sub.α -type,1,15-lactone; a formula LXIX 8β,12α-PGE-type, 1,15-lactone; a formulaLXXI 8β,12α-PGF.sub.β -type, 1,15-lactone; or a formula LXXIII8β,12α-PGD-type, 1,15-lactone. Additionally, the transformations of theformula LXI compound to the formula LXII compound are optionallyemployed on the 8,12-isomers of those depicted by formulas LXI to LXIV,respectively, thereby preparing the PGF.sub.α -type, 1,15-lactonecorresponding to formula LXIV.

The transformation of the formula LXI compound to the formula LXIIcompound of Chart D proceeds by the method described in Chart B for thepreparation of the formula XXXII compound from the formula XXXIcompound. Thereafter, the formula LXXII compound is 1,15-lactonized,forming the formula LXIII compound. This lactonization proceeds by themethods hereinabove described. Thereafter, the formula LXIII compound isdecyclo(alkylboronized) employing the procedure described in Chart B forthe transformation of the formula XXXIII compound to the formula XXXIVcompound. Accordingly, the 8β,12α -PGF.sub.α -type, 1,15-lactones areprepared.

Thereafter, the formula LXIV compound is transformed to the formula LXVcompound by selective silylation of the C-9 hydroxy over the C-11hydroxy. This selective silylation proceeds by methods known in the art.For example, see U.S. Pat. No. 3,822,303, issued July 2, 1974, GermanOffenlegungsschrift, No. 2,259,195 (Derwent Farmdoc CPI No. 36457U-B) orNetherlands Pat. No. 7,214,142 (Derwent Farmdoc CIP No. 26221U-B).Thereafter, the formula LXV compound is employed in the preparation ofeither the formula LXVI compound or the formula LXXII compound.

The formula LXV compound is transformed to the formula LXVI compound byreplacing the 11-hydroxy hydrogen with a blocking group according toR₁₀. Methods known in the art, hereinabove described, are employed.

The formula LXVI compound is then transformed to the formula LXVIIcompound by selective hydrolysis of the silyl group over the blockinggroup according to R₁₀. Methods hereinabove described for such selectivehydrolysis are employed. See the transformation of the formula XLIVcompound to the formula XLVI compound of Chart C.

Thereafter, the formula LXVII compound is transformed to the formulaLXVIII compound by oxidation of the 9-hydroxy to a corresponding 9-oxocompound. Reagents and procedures known in the art for transformation ofPGF.sub.α -type compounds to PGE-type compounds are employed. Theformula LXVIII compound is then hydrolyzed, whereby blocking groupsaccording to R₁₀ are removed, thereby preparing the formula LXIX8β,12α-PGE-type, 1,15-lactone. Methods of hydrolysis of blocking groupsaccording to R₁₀ hereinabove described are employed.

Thereafter the formula LXIX compound is transformed to the formula LXXIcompound by a ring carbonyl reduction, employing methods known in theart for the transformation of PGE-type compounds to the correspondingPGF.sub.β compounds. Accordingly, sodium, potassium, or lithiumborohydride is employed in the reduction, followed by chromatographicseparation of the 9β-hydroxy epimer from the 9-epimeric mixture soformed. Accordingly, there is prepared 8β,12α-PGF.sub.β -type,1,15-lactones of formula LXXI.

The formula LXV compound is employed in the preparation of the formulaLXXII compound by selective oxidation of the C-11 hydroxy to acorresponding oxo. Methods described in Chart G and the transformationof formula LXVII compound to the formula formula LI compound areemployed. Thereafter the formula LXXII compound is transformed to theformula LXXIII 8β,12α-PGD-type, 1,15-lactone following proceduresdescribed above for hydrolysis of silyl groups.

Chart E provides a method whereby the formula LXXXI PGE- or11-deoxy-PGE-type starting material is transformed to the formula IxxxiiPGE- or 11-deoxy-PGE-type, 1,15-lactones, or the formula LXXXV PGF.sub.α-, 11-deoxy-PGF.sub.α -, PGF.sub.β -, or 11-deoxy-PGF.sub.β -type,1,15-lactones. Further, Chart E describes the use of the formula LXXXIII8β,12α-PGE- or 11-deoxy-8β,12α-PGE-type compound in the preparation ofthe formula LXXXIV 8β,12α-PGE- or 11-deoxy-8β,12α-PGE-type,1,15-lactones or the formula LXXXVI 8β,12α-PGF.sub.α -,11-deoxy-8β,12α-PGF.sub.α -, 8β,12α-PGF.sub.β -, or11-deoxy-8β,12α-PGF.sub.β -type, 1,15-lactones.

For the transformation of the formula LXXXI or LXXXIII compound to theformula LXXXII or formula LXXXIV compound, respectively, lactonizationmethods hereinabove described are employed. Thereafter, the formulaLXXXIV or formula LXXXVI compound is prepared from the formula LXXXIIIcompound, respectively, by a ring carbonyl reduction, followed byseparation of C-15 epimers. These ring carbonyl reductions and epimericseparations are performed by methods described hereinabove. See thetransformation of the formula XLIII compound to the formula LXIVcompound of Chart C.

Chart F provides a method whereby the formula XCI PGE-type compound istransformed to the formula XCII PGA-type, 1,15-lactone; the formulaXCIII 8β,12α-PGE-type, 1,15-lactone is transformed to the formula XCIV8β,12α-PGA-type, 1,15-lactone; a formula XCV PGD-type, 1,15-lactone istransformed to a formula XCVI 9-deoxy-9,10-didehydroPGD-type,1,15-lactone; or a formula XCVII 8β,12α-PGD-type, 1,15-lactone istransformed to a formula XCVIII 9-deoxy-9,10-didehydro-8β,12α-PGD-type,1,15-lactone.

For each of the above transformations of Chart F, the hydroxyl on thecyclopentane ring is dehydrated to the corresponding compound withα,β-unsaturation to the ketone employing mild acidic dehydration. Forexample, methods known in the art for the transformation of PGE-typecompounds to PGA-type compounds are employed. Alternatively, the variousstarting materials of Chart F are transformed to corresponding acetates(e.g. employing acetic anhydride), and thereafter chromatographed onsilica gel to effect the desired dehydration.

Chart G provides a method whereby the formula CI PGA-type compound,formula CII PGB-type compound, formula CIII, formula CV11-deoxy-PGE-type compound, or their respective 8β,12α-isomers, aretransformed to a corresponding formula CVI PG-type, 1,15-lactone whereinthe cyclopentane ring structure of the starting material is preserved.Since each of the formula CI to formula CV compounds ismonohydroxylated, lactonization proceeds by the general methodsdescribed hereinabove without the use of any selective blocking.

With respect to Chart H, a method is provded whereby the formula CXIPGF.sub.α -type compound is transformed to a formula CXIX PGF.sub.α-type, 1,11-lactone, formula CXXII PGE-type, 1,11-lactone, or formulaCXXIII PGF.sub.β -type, 1,11-lactone.

With respect to Chart H, the transformation of the formula CI compoundto the formula CIV compound employs the methods hereinabove described inChart B for the transformation of the formula XXXI compound to theformula XXXIV compound. Thereafter, the formula CXV compound is preparedfrom the formula CXIV compound by selective silylation. Accordingly,methods described in Chart C for the transformation of the formula XLIcompound to the formula XLII compound are employed.

Thereafter the formula CXV compound is transformed to the formula CXVIcompound by transformation of the 9-hydroxy hydrogen to a blocking groupaccording to R₁₀. Methods described hereinabove are employed.Thereafter, the formula CXV compound is transformed to the formula CXVIcompound by selective hydrolysis of the 11-silyl group. Methodsdescribed hereinabove are employed. See, the transformation of theformula XLV compound to the formula XLVI compound in Chart C.

Thereafter, the formula CXVII compound is 1,11-lactonized, therebyforming the formula CXVIII compound. This lactonization proceeds bymethods known in the art and described hereinabove.

Thereafter, the formula CXIX PGF.sub.α -type, 1,11-lactone is preparedfrom the formula CXVIII compound by hydrolysis of a blocking groupsaccording to R₁₀. Methods known in the art and hereinabove described areemployed.

Thereafter, the formula CXX compound is prepared from the formula CXIXcompound by selective silylation. This selective silylation of the C-15hydroxyl over the C-9 hydroxyl is accomplished by methods known in theart and described and referenced in Chart C for the transformation ofthe formula CXLI compound to the formula CXLII compound. Thereafter, theformula CXX compound is oxidized at the C-9 position to thecorresponding formula CXXI compound employing methods known in the artfor the transformation of PGF.sub.α -type compounds to correspondingPGE-type compounds. Thereafter, the formula CXXII PGE-type, 1,11-lactoneis prepared by hydrolysis of the silyl group, employing methods known inthe art.

Finally, the formula CXXIII PGF.sub.β -type, 1,11-lactones are preparedfrom the formula CXXII PGE-type, 1,11-lactones by ring carbonylreduction and separation of the 9-epimeric mixture thereby obtained.Accordingly, methods described hereinabove, i.e. the transformation ofthe formula XLIII compound to the formula XLIV compound of Chart C, areemployed.

Chart J provides a method whereby formula CXXXI 8β,12α-PGF.sub.α -typecompound is transformed to a formula CXXXVI 8β,12α-PGF.sub.α -,8β,12α-PGF.sub.β -, or 8β,12α-PGE-type, 1,11-lactone.

With respect to Chart J, the formula CXXXI compound is transformed tothe formula CXXXII compound by a selective etherification at C-15.Methods described in proceeding charts are employed. See thetransformation of the formula XXXI compound to the formula XXXIVcompound of Chart B. Thereafter, the formula CXXXII compound isselectively silylated at the C-9 position, thereby preparing the formulaCXXXIII compound. This selective silylation proceeds by the methoddescribed in the transformation of the formula LXIV compound to theformula LXV compound of Chart D.

Thereafter, the formula CXXXIII compound is transformed to the formulaCXXXIV compound by 1,11-lactonization, employing the lactonizationprocedures described hereinabove. Thereafter the formula CXXXV compoundis prepared from the formula CXXXIV compound by selective hydrolysis ofthe silyl group in the presence of a blocking group according to R₁₀.Methods described in Chart C in the transformation of the formula CXLVcompound to the formula CXLVI compound are employed.

Thereafter, the formula CXXXV compound is transformed to the formulaCXXXVI compound employing methods hereinabove described in thetransformation of PGF.sub.α -type lactones to corresponding PGE-type andPGF.sub.β -type lactones.

Chart K provides a method whereby the formula CXLI compound or its8β,12α-isomer is transformed to the corresponding formula CXLVIIIPG-type 1,11-lactone or its 8β,12α-epimer.

With respect to Chart K the formula CXLI starting material is preparedin the manner of the formula XXXV compound of Chart B when M₁₅ is thesame as M₈. The 8β,12α-compound wherein M₁₅ is the same as M₈corresponding to formula CXLI is prepared in the manner of the formulaXXXV compound of Chart B employing 8β,12α-PGF.sub.α -type startingmaterial corresponding to formula XXXI.

When M₁₅ is the same as M₇ for the formula CXLI compound of Chart K,then the formula CXLI compound is prepared by selective silylationemploying the method described in Chart H for the preparation of theformula CXX compound from the formula CXIX compound.

The formula CXLII compound is prepared from the formula CXLI compound bysilylation at C-9. Methods known in the art for the introduction ofsilyl groups are employed. Thereafter, the formula CXLIII compound isprepared from the formula CXLII compound by reduction of the 11-oxo toan 11-hydroxy. This reduction proceeds by methods herein described forthe transformation of PGE-type compounds to corresponding PGF-typecompounds. Finally, the formula CXLIV compound is prepared from theformula CXLIII compound by separation of the 11-epimeric mixtureemploying silica gel chromatography.

The formula CXLIV compound is then 1,11-lactonized forming the formulaCXLV compound. This lactonization proceeds by the general methodshereinabove described. Thereafter, the formula CXXXV compound istransformed to CXXXVI compound by hydrolysis of the silyl groups. WhenM₁₅ is the same as M₈, this hydrolysis proceeds selectively by methodshereinabove described. See the transformation of the formula CXLVcompound to the formula CXLVI compound of Chart C. Otherwise, methodsgenerally known in the art for removal of silyl groups, withouthydrolyzing ester linkages, are employed.

Thereafter, the formula CXLVI compound wherein M₁₆ is the same as M₈ istransformed to the formula CXLVII compound, employing methodshereinabove described for the transformation of PGF.sub.α -typecompounds to PGE-type compounds. Finally, the formula CXLVII compound istransformed to the various formula CXLVIII PG-type, 1,11-lactonesemploying ring transformations hereinabove described and hydrolyzing theblocking group according to R₁₀, following procedures hereinabovedescribed.

Chart L provides a method whereby the formula CLI PGE-type 1,15-lactone,or its 8β,12α-isomer is transformed to a corresponding formula CLVII9β-PGD- or PGD-type, 1,15-lactone or its 8β,12α-isomer, respectively.

With respect to Chart L the formula CXLII compound is prepared from theformula CXLI compound by silylation. Methods known in the art andhereinabove described are employed. The formula CXLIII is then preparedfrom the formula CXLII compound by a ring carbonyl reduction, employingmethods hereinabove described. The 9-epimeric mixture thusly prepared isthen separated by silica gel chromatography, preparing the separatedformula CLIII epimers.

The formula CLIV compound is then prepared from the formula CLIIIcompound by transforming the 9-hydroxy hydrogen to a blocking groupaccording to R₁₀. Methods described hereinabove are employed.

Thereafter the silyl groups are selectively hydrolyzed over the blockinggroups according to R₁₀, following procedures described in Chart B forthe transformation of the formula CXLV compound to the formula CXLVIcompound. Thereupon, the formula CXLV compound is oxidized at the C-11position to the corresponding 11-oxo compound. Methods hereinabovedescribed, particularly the transformation of the formula XXXV compoundto the formula XXXVI compound of Chart B are employed.

Thereafter, the 9β-PGD- or PGD-type, 1,15-lactones of formula CXLVII areprepared from the formula CXLVI compound by hydrolysis of the blockinggroups according to R₁₀. Methods known in the art and hereinabovediscussed are employed.

Chart M provides a method whereby the formula CLXI PGF.sub.α -typecompound is transformed to a formula CLXVII 9β-PGD-type, 1,9-lactone.

With respect to Chart M the formula CLXI compound is available asformula XXXIV of Chart B. Thereafter, this compound is transformed tothe formula CLXII compound by selective silylation of the C-11 hydroxyover the C-9 hydroxy, employing methods described in Chart C (thetransformation of the formula XLI compound to the formula XLIIcompound).

Thereafter, the formula CLXII compound undergoes a 9-epimerization toform the formula CLXIII PGF.sub.β -type compound. This epimerization isaccomplished by one of several methods known in the art. For example,the formula CLXII compound is optionally oxidized to a 9-oxo compound,and thereafter the 9-oxo compound reduced to the corresponding 9-hydroxyepimeric mixture. Alternatively, the method of E. J. Corey, et al., J.Chem. Soc., Chemical Communications 658 (1975) is employed.

Thereafter the formula CLXIII compound is 1,9-lactonized to the formulaCLXIV compound. Lactonization procedures described hereinabove areemployed. Thereafter the formula CLXV compound is prepared from theformula CLXIV compound by selective hydrolysis of the silyl group in thepresence of blocking groups according to R₁₀. Procedures employed inChart C for the transformation of the formula LXV compound to theformula LXVI compound are employed. Thereafter, the formula CLXVIcompound is prepared from the formula CLXV compound by oxidation of the11-hydroxy to an 11-oxo. This oxidation proceeds by methods described inChart B for the transformation of the formula XXXV to the formula XXXVIcompound.

Thereafter, formula CXXXVII PGD-type, 1,9-lactone is prepared from theformula CXXXVI compound by hydrolysis of the blocking group according toR₁₀ employing methods hereinabove described.

Chart N provides a method whereby the formula CLXXI 8β,9β,12α-PGF-type,1,9-lactone is transformed to the corresponding 8β,9β,12α-PGD-type,1,9-lactone of formula CLXXIV.

With respect to Chart N the formula CLXXII compound is prepared from theformula CLXXI compound by selective silylation of the C-15 hydroxy. Thisselective silylation accomplished by the procedure described in Chart Jfor the transformation of the formula CLXIX compound to the formula CLXXcompound. Thereafter the formula CLXXIII compound is prepared from theformula CLXXII compound by oxidation of the 11-hydroxy to an 11-oxo.This oxidation is accomplished by methods described in Chart B in thetransformation of the formula XXXV compound to the formula XXXVIcompound.

Thereafter, the formula CLXXIV 8β,9β,12α-PGD-type, 1,9-lactone is thenprepared from the formula CLXXIII compound by hydrolysis of the silylgroup at C-15. The hydrolysis proceeds by those methods known in the artto remove silyl groups while not affecting ester linkages.

Chart O provides a method whereby the formula CLXXVI9-deoxy-9,10-didehydro-PGD-type, 1,15-lactone is transformed to acorresponding formula CLXXVIII 9-deoxy-PGD-type, 1,15-lactone.Alternatively, 9,10-didehydro-9-deoxy-8β,12α-PGD-type compounds areemployed in place of the formula CLXXVI starting material preparingcorresponding 9-deoxy-8β,12α-PGD-type products.

The formula CLXXVII starting material or its 8β,12α-isomer is preparedby dehydration of a corresponding PGD- or 8β,12α-PGD-type, 1,15-lactone.This dehydration proceeds by mild acid catalysis, employing organicacids such as acetic acid, trifluoroacetic acid, citric acid, oxalicacid, or p-toluenesulfonic acid. This dehydration proceeds rapidly attemperatures between ambient temperature at about 40° C. Alternatively,the dehydration is affected by allowing the formula CLXXVI startingmaterial (or its 8β,12α-isomer) to stand on a column of acid washedsilica gel.

The reaction sequence of Chart O proceeds by methods known in the artfor transforming PGA-type compounds to corresponding 11-deoxy-PGE-typecompounds. Accordingly, the formula CLXXVI starting material issubjected to a potassium, sodium, or lithium borohydride reduction as isknown in the art. For this purpose, for example, the reaction is carriedout at about -20° C., and is ordinarily complete within a few mintues.Thereafter, the formula CLXXVII compound, thusly obtained, is oxidizedto the formula CLXXVIII 9-deoxy-PGD-type, 1,15-lactone employingoxidation agents known in the art for this purpose. Thus, for example,the Jones or Collins reagent as described above, are employed.

Chart P provides a method whereby the formula CLXXXIII 11β-PGF .sub.β-type compound (or its 8β,12α-isomer) is transformed to a formulaCLXXXVIII 9β-PGD-type, 1,9-lactone (or a corresponding 8β,9β,12α-PGD-type, 1,9-lactone).

With respect to Chart P the formula CLXXXIII compound is known in theart or prepared by methods known in the art. For example, itspreparation proceeds from the formula CLXXXI PGA-type compound by9,10-epoxidation, reduction of the expoxide to an (11RS)-hydroxy mixtureand chromatographic separation of the 11β-hydroxy compound from theepimeric mixture. This reaction sequence, preparing the formula CLXXXIIcompound, is then followed by a ring carbonyl reduction, yielding theformula CLXXXIII starting material. When the 8β,12α -isomer of theformula CLXXXIII compound is desired, such compounds are known in theart or prepared by methods known in the art as enantiomers or 15-epienantiomers of PGF₂α -type compounds. Methods for epoxidation, reductionof the epoxide, and separation of the epimeric mixture of alcohol soformed are described in Belgium Pat. No. 804,837 (Derwent Farmdoc CPINo. 22865V).

This formula CLXXXIII compound is then cyclo(alkylboronized) to theformula CLXXXIV compound, following the procedure described in Chart Bfor the preparation of the formula XXXII compound from the formula CXXXIcompound. Thereafter, the formula CLXXXIV compound is transformed to theformula CLXXXV compound by the procedure described in Chart B for thepreparation of the formula CXXXIV compound from the formula CXXXIIcompound. This C-15 selectively protected formula CLXXXV compounds isthen 1,9-lactonized to a corresponding formula CLXXXVI compound,employing the lactonization procedures described hereinabove.Thereafter, the formula CLXXXVI compound is converted to the formulaCLXXXVIII compound employing the method described in Chart B for thepreparation of the formula XXXVII compound from the formula XXXVcompound.

Chart R provides a method whereby the formula CXCVI 15-methyl-PGF.sub.α,1,11-lactone is conveniently prepared from the formula CXCI15-methyl-PGF.sub.α -type compound.

With regard to Chart R, the formula CXCII compounds is prepared from theformula CXCI compound by selective acylation. This selective acylationis achieved by employing a single equivalent of the acylating agent(e.g. acyl chloride) and terminating the reaction promptly after theselective C-11 protection is effected. General methods described abovefor the introduction of acyl protecting groups are employed.

Thereafter, the formula CXCIII compound is prepared from the formulaCXCII compound by silylation. Silylation procedures known in the art areemployed. Thereafter, the formula CXCIV compound is prepared from theformula CXCIII compound by selective removal of the acyl protectinggroup according to R₉. This selective removal of the acyl protectinggroup is accomplished employing potassium, sodium, or lithium hydroxidein aqueous methanol, as described above.

Thereafter, the formula CXCV compound is prepared from the formula CXCIVcompound by 1,11-lactonization. This lactonization proceeds ashereinabove described. Finally, formula CVI compound is prepared fromthe formula CXV compound by removal of the silyl groups, as hereinabovedescribed.

With the exception of the procedure in Chart R, where the 15-hydroxyhydrogen is replaced on a 15-methyl-PG-type compound, or, in Charts H,J, and K where PG-type, 1,11-lactones are prepared, the introduction ofsilyl groups or blocking groups according to R₁₀ in place of the hydroxyhydrogen at C-15 is not required for the various transformations of theabove charts when the 15-methyl compounds are employed. Accordingly,when the 15-hydroxy hydrogen is the only hydroxy hydrogen to be blockedor silylated, then such blocking or silylation may be omitted. Further,when one or both of any secondary hydroxyls at C-9 or C-11 are to beblocked or silylated in addition to the C-15 tertiary hydroxyl, then thetransformation effecting the blocking or silylation need only be carriedout until any secondary hydroxyls have been so transformed.

However, when the hydroxy hydrogen of a 15-methyl-PG-type compound isreplaced with a blocking group according to R₁₀, then the subsequenthydrolysis of the blocking group in many cases epimerizes the C-15hydroxyl. In such cases, epimeric purity of the product then requiresseparation employing silica gel chromatography, high pressure liquidchromatography, or other techniques known to separate prostaglandin-typediastereomers.

The present invention particularly provides a prostaglandin-type1,9-lactone of the formula ##STR96## wherein Z₁, W₂, Y₁, M₁, L₁, and R₇are as defined above.

Each of the various prostaglandin-type, 1,9-lactones of the presentinvention is useful for each of the corresponding purposes for which thecorresponding free acid of each of these lactones is used. Inparticular, these protaglandin-type, 1,9-lactones are administered bythe same routes as the corresponding free acids and for each particularpurpose are administered in doses of about 5 to 1000 times the dosage atwhich the corresponding free acid is admistered by the same route.

Surprisingly and unexpectedly, however, in administering variousprostaglandin-type, 1,9-lactones herein the host experiences increasedtolerance of drug and fewer undesirable side effects associated witheach respective route of administration. For example, when theprostaglandin-type, 1,9-lactones of the present invention areadministered intravenously, higher infusion rates are successfullyemployed with reduction or elimination of undesirable local effectsassociated with administration of the corresponding free acid.

Additionally, when intramuscular administration is employed, the presentPG-type, 1,9-lactones provide more consistent release rates from theinjection site and in particular a more prolonged duration of releasethan the corresponding free acid. Accordingly, the presentprostaglandin-type, 1,9-lactones exhibit surprisingly and unexpectedlyprolonged activity when administered by this route.

The PGD-type, 1,9-lactones and 8β,12α -PGD-type, 1,9-lactones areaccordingly surprisingly and unexpectedly more useful blood pressurelowering agents, gastric antisecretory agents, and platelet aggregationinhibiting agents, than the corresponding free acids. Most particularlythese lactones exhibit surprisingly improved stability, both as bulkchemicals and finished pharmaceutical formulations. Further, whenadministered at therapeutic doses, these lactones exhibit a surprisinglyand unexpectedly more sustained duration of action than thecorresponding free acids, an improved therapeutic ratio, and a lowerincidence of prostaglandin-related gastrointestinal and bronchopulmonaryside effects than the correspnding free acids. Accordingly, thesecompounds are surprisingly and unexpectedly more useful than thecorresponding free acids in the treatment of hypertension,gastrointestinal hyperacidity, gastrointestinal ulcers and coagulativedisorders of the cardiovascular system.

The PGF.sub.α -type, 1,9-lactones; 8β,12α-PGF.sub.α -type, 1,9-lactones;11-deoxy-PGF.sub.α -type, 1,9-lactones; 11-deoxy-8β,12α-PGF.sub.α -type,1,9-lactones; PGF.sub.β -type, 1,9-lactones; 8β,12α-PGF.sub.β -type,1,9-lactones; 11-deoxy-PFG.sub.β -type, 1,9-lactones; and11-deoxy-8β,12α-PGF.sub.β -type, 1,9-lactones are accordinglysurprisingly and unexpectedly more useful than the corresponding freeacids when used as nasal decongestants, oxytocic agents, regulators ofthe mammalian reproductive cycle, and inhibitors of inflammatoryproliferative dermatosis (such as psoriasis), in that these lactonesexhibit a prolonged duration of activity. Thus, these lactones aresurprisingly and unexpectedly more useful than the corresponding freeacids in including menstruation terminating pregnancy, and preventingexcessive postpartium bleeding. In addition to the surprisingly andunexpectedly prolonged duration of activity, these compounds attherapeutic doses also exhibit a decreased incidence ofprostaglandin-associated gastrorintestinal side effects, particularlynausea, vomiting and diarrhea, and when used as oxytocic agents, orotherwise as regulators of mammalian reproductive cycle, a lowerincidence of cardiovascular or pulmonary side effects is evident.

These PGF-, or 11-deoxy-PGF-type, 1,9-lactones or their 8β,12α-isomersadditionally produce hyperthermic or hypothermic responses andaccordingly in initiating treatment with these lactones it is especiallyimportant to monitor body temperature, adjusting dosages so that theabsolute change in body temperature from normal is less than or equal to1.5° to 2° C. Acccordingly, administration of the lactone isdiscontinued or the rate of administration decreased in the eventexcessive body temperature changes appear imminent.

Thus, the various lactones described above are employed for the abovedescribed purposes being administered orally, vaginally, topically,internasally, interamniotically, or parenterally and being formulated astablets, capsules, nosedrops, aerosols, creams, ointments, suppositoriesor oral-based or water-based solutions or suspensions, as is known inthe art for corresponding administration and formulation ofcorresponding free acids or their alkyl esters.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention can be more fully understood by the following examples andpreparations.

All temperatures are in degrees centigrade. IR (infrared) absorptionspectra are recorded on a Perkin-Elmer Model 421 infraredspectrophotometer. Except when specified otherwise, undiluted (neat)samples are used.

UV (Ultraviolet) spectra are recorded on a Cary Model 15spectrophotometer.

NMR (Nuclear Magnetic Resonance) spectra are recorded on a Varian A-60,A-60D, and T-60 spectrophotometer on deuterochloroform solutions withtetramethylsilane as an internal standard (downfield).

Mass spectra are recorded on an CEC model 21-110B Double Focusing HighResolution Mass Spectrometer on an LKB Model 9000 Gas-Chromatograph-MassSpectrometer. Trimethylsilyl derivatives are used, except whereotherwise indicated.

The collection of chromatographic eluate fractions starts when theeluant front reaches the bottom of the column. "Brine", herein, refersto an aqueous saturated sodium chloride solution.

The A-IX solvent system used in thin layer chromatography is made upfrom ethyl acetate-acetic acid-cyclohexane-water (90:20:50:100) asmodified from M. Hamberg and B. Samuelsson, J. Biol, Chem 241, 257(1966).

Skellysolve B (SSB) refers to mixed isomeric hexanes.

Silica gel chromatography, as used herein, is understood to includeelution, collection of fractions, and combination of those fractionsshown by TLC (thin layer chromatography) to contain the pure product(i.e., free of starting material and impurities).

Melting points (MP) are determined on a Fisher-Johns or Thomas-Hoovermelting point apparatus.

DDQ refers to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

THF refers to tetrahydrofuran.

Specific Rotations, [α], are determined for solutions of a compound inthe specified solvent at ambient temperature with a Perkin-Elmer Model141 Automatic Polarimeter.

EXAMPLE 1 PGF₂α , 1,9-lactone

(Formula XXII: Z₁ is cis--CH═CH--(CH₂)₃ --, R₈ is hydroxy, Y₁ istrans--CH═CH--, R₃ and R₄ of the L₁ moiety and R₅ of the M₁ moiety areall hydrogen, and R₇ is n-butyl).

Refer to Chart A.

A. A solution of 35 mg. of PGF₂α, 39 mg. of triphenylphosphine, and 33mg. of 2,2'-dipyridyl disulfide in 0.5 ml. of dry, oxygen-free benzeneis stirred at 25° C. for 18 hr. The resulting mixture is thereafterdiluted with 25 ml. of benzene and heated at reflux for 24 hr. Thinlayer chromatographic analysis in (15 percent acetone and methylenechloride) indicates a mixture of PGF₂α, 1,9-lactone and 1,15-lactone ina ratio of about 8 to one. Pure product is then isolated from thereaction mixture employing silica gel chromatographic separation.

B. Formation of PGF₂α, 1,9-lactone employing an 11,15-bis ether startingmaterial.

1. a solution of 496 mg. of PGF₂α, 1,11-bis(α-ethoxyethyl ether) in 5ml. of anhydrous, oxygen free xylene is treated with 330 mg. of2,2-dipyridyl disulfide and 393 mg. of triphenylphosphine. This mixtureis then stirred for 2.5 hr. at 25° C. under an atomosphere of nitrogen.The resulting mixture is then diluted with 250 ml. of dry, oxygen-freexylene and heated at reflux for 18 hr. Followed by removal of xyleneunder reduced pressure, the residue is diluted with aqueous sodiumbicarbonate and extracted with hexane. The combined hexane layers arewashed with brine, dried over anhydrous sodium sulfate, andconcentrated.

2. The crude product of (1) above is then dissolved in 40 ml. oftetrahydroufran and 30 ml. of water. This mixture is then treated with 6ml. of 85 percent phosphoric acid and stirred under a nitrogenatmosphere at 40° C. for 2.5 hr. After then removing most of thetetrahydrofuran at reduced pressure, the residue is diluted with ethylacetate and aqueous sodium bicarbonate and the title product is isolatedby extraction with ethyl acetate. The combined organic phases are thenwashed with aqueous sodium bicarbonate, and brine; dried over magnesiumsulfate; and concentrated. Crude product is then chromatographed on 50g. of neutral silica gel. The column is packed with ethyl acetate andhexane (1:1) and eluted with pure ethyl acetate. Thereupon 500 mg. ofpure product are obtained. This material is then rechromatographed on asilica gel column packed in 10 percent acetone and methylene chlorideand eluted with 10 to 35 percent acetone in methylene chloride.Thereupon 210 mg. of pure PGF₂α, 1,9-lactone are obtained. Infraredabsorptions are observed at 3460, 3000, 1730, 1705, 1335, 1285, 1230,1210, 1180, 1150, 1085, 1065, 1025, 970, and 720 cm.⁻¹. Mass spectrumshows peaks at 318, 300, 289, 274, 247, 229, 219, and 192.

Following the procedure of Example 1, but employing in each of thevarious PGF₂α -type compounds described by formula 1 in place of PFG₂α,there are obtained each of the various corresponding PGF₂α,1,9-lactones.

EXAMPLE 2 8β,12α-PGF₂α, 1,9-lactone.

(Formula XXIV: Z₁, R₈, Y₁, M₁, L₁, and R₇ are as defined in Example 1).

Refere to Chart A.

Following the procedure of either Example 1, part A or Example 1, partB, 8β,12α-PGF₂α or an 8β,12α-PGF₂α, 11,15-bis ether, respectively, istransformed to the title product.

Following the procedure of Example 2, but employing each of the various8β,12α-PGF₂α -type compounds described by formula 1 in place of8β,12α-PGF₂α, there are obtained each of the various corresponding8β,12α-PGF₂α -type, 1,9-lactones.

EXAMPLE 3 PFG₂β, 1,9-lactone

(Formula XXII: Z₁, R₈, Y₁, M₁ L₁, and R₇ are as defined in Example 1).

Refer to Chart A.

Following the procedure of Example 1, part A or Example 1, part B, butusing PGF₂β or a PFG₂β 11,15-bis ether there is prepared the titleproduct.

Following the procedure of Example 3, but employing each of the variousPGF₂β -type compounds described by formula 1 in place of PGF₂β, thereare obtained each of the various corresponding PGF₂β -type,1,9-lactones.

EXAMPLE 4 8β,12α-PGF₂β, 1,9-lactone

(Formula XXIV: Z₁, R₈, Y₁, M₁, L₁, and R₇ are the same as in Example 1).

Refer to Chart A.

Following the procedure of Example 1, part A, or Example 1, part B, butusing 8β,12α-PGF₂β or an 8β,12α-PGF₂β, 11,15-bis ether there is obtainedthe title product.

Following the procedure of Example 4, but employing each of the variousPGF₂β -type compounds described by formula 1 in place of 8β,12α-PFG₂β,there are obtained each of the various corresponding 8β,12α-PGF₂β -type,1,9-lactones.

EXAMPLE 5 11-Deoxy-PGF₂α, 1,9-lactone (Formula XXII: Z₁, Y₁, M₁, L₁, andR₇ are as defined in Example 1, and R₈ is hydrogen).

Refer to Chart A.

Following the procedure of Example 1, part A or Example 1, part B, butemploying 11-deoxy-PGF₂α or an 11-deoxy-PGF₂α, 15-ether there isobtained the title product.

Following the procedure of Example 5, but employing each of the various11-deoxy-PGF₂α -type compounds described by formula 1 in place of11-deoxy-PGF₂α, there are obtained each of the various corresponding11-deoxy-PGF₂α -type, 1,19-lactones.

EXAMPLE 6 11-Deoxy-8β,12α-PGF₂α, 1,9-lactone

(Formula XXIV: Z₁, R₈, Y₁, M₁, and R₇ are as defined in Example 5).

Refer to Chart A.

Following the procedure of Example 1, part A, or Example 1, part B, butemploying 11-deoxy-8β,12α-PGF₂α or an 11-deoxy-8β,12α-PGF₂α, 15-ether,respectively, there is obtained the title product.

Following the procedure of Example 6, but employing each of the various11-deoxy-8β,12α-PGF₂α -type compounds described by formula 1 in place of11-deoxy-8β,12α-PGF₂α, there is obtained each of the variouscorresponding 11-deoxy-8β,12α-PGF₂α -type, 1,9-lactones.

EXAMPLE 7 11-deoxy-PGF₂β, 1,9-lactone

(Formula XXII: Z₁, R₈, Y₁, M₁, L₁, and R₇ are as defined in Example 5).

Refer to Chart A.

Following the procedure of Example 1, part A or Example 1, part B, butemploying 11-deoxy-PGF₂β or an 11-deoxy-PGF₂β, 15-ether, respectively,there is obtained the title product.

Following the procedure of Example 7, but employing each of the various11-deoxy-PGF₂β -type compounds described by formula I in place of11-deoxy-PGF₂β, there is obtained each of the various corresponding11-deoxy-PGF₂β -type, 1,9-lactones.

EXAMPLE 8 11-deoxy-8β,12α-PGF₂β, 1,9-lactone

(Formula XXIV: Z₁, R₈, Y₁, M₁, L₁, and R₇ are as defined in Example 5).

Refer to Chart A.

Following the procedure of Example 1, part A or Example 1, part B, butemploying 11-deoxy-8β,12α-PGF₂β or an 11-deoxy-8β,12α-PGF₂β, 15-ether,respectively, there is obtained the title product.

Following the procedure of Example 8, but employing each of the various11-deoxy-8β,12α-PGF₂β -type compounds described by formula I in place of11-deoxy-8β,12α-PGF₂β, there is obtained each of the variouscorresponding 11-deoxy-8β,12α-PGF₂β -type 1,9-lactones.

EXAMPLE 9 PGD₂, 1,9-lactone

(Formula XXXVII: Z₁, Y₁, M₁, L₁, and R₇ are as defined in Example 1).

Refer to chart B.

A. PGF₂α (2 g.) in 15 ml. of methylene chloride is mixed withn-butylboronic acid (688 mg.). This reaction mixture is then heated atreflux with vigorous stirring adding methylene chloride and 5 ml.aliquots to replace amounts allowed to escape by evaporation. After 25min., 10 ml. of dihydropyran is added to the reaction mixture with 150mg. of pyridine hydrochloride. After about 20 hr. etherification iscomplete and methylene chloride is removed under reduced pressure. Theresidue is then diluted with 30 ml. of methanol and 13 ml. of 3N aqueouspotassium hydroxide. The resulting clear yellow solution is then allowedto stand for 2 hr., then treated with 5 ml. of a 30 percent solution ofaqueous hydrogen peroxide and 30 ml. of water. Thereafter the methanolis removed under reduced pressure and the aqueous residue diluted with100 ml. of water and extracted twice with diethyl ether. The aqueouslayer is then acidified with 25 ml. of 2N aqueous potassium bisulfateand extracted with ethyl acetate. The combined organic extracts are thenwashed with brine and dried over sodium sulfate. Removal of the solventunder reduced pressure yields 3.3 g. of an oil which is thenchromatographed on 100 g. of acid washed silica gel. Eluting with 75percent ethyl acetate in hexane, 2.0 g. of pure formula XXXIV PGF₂α,15-(tetrahydropyranyl ether) is obtained.

B. A solution of 1.7 g. of the reaction product of part A, 1.52 g. oftriphenylphosphine, and 1.28 g. of 2,2'-dipyridyl disulfied in 10 ml. ofdry, oxygen-free benzene is stirred at room temperature overnight. Thenthe solution is diluted with 1 l. of oxygen free benzene and the mixtureis refluxed under a nitrogen atmosphere for 23 hr. After cooling to roomtemperature, the mixture is concentrated to an oil. The crude productthus obtained is chromatographed on a column of 450 g. of silica gel,packed with 30 percent ethyl acetate in hexane. Eluting with 50 to 60percent ethyl acetate in hexane, 1.23 g. of the formula XXXV 1,9-lactoneis obtained. Silica gel R_(f) is 0.26 in 50 percent ethyl acetate inhexane. Infrared absorptions are observed at 3500, 2980, 2910, 1750,1580, 1530, 1450, 1420, 1360, 1345, 1320, 1260, 1230, 1200, 1180, 1120,1080, 1020, 990, 970, 940, 905, 870, and 815 cm.⁻¹.

C. A solution of 5.5 g. of the reaction product of part B in acetone iscooled to -30° C. Thereupon 3.6 ml. of the Jones reagent is added andthe solution is maintained at -30° C. for 1 hr. Thereafter, 6 ml. ofisopropyl alcohol is added and the solution is stirred for another 30min. at -30° C. The mixture is then poured into 600 ml. of ice water andextracted with diethyl ether and hexane (1:2). This organic extract isthen washed three times with brine, dried over magnesium sulfate, andconcentrated to an oil (5 g.). This crude oil is then chromatographed on375 g. of silica gel, packed with 10 percent ethyl acetate in hexane,and eluted with 25 percent ethyl acetate and hexane. Thereupon, 3.4 g.of the formula XXXVI compound are obtained as a colorless oil. Silicagel R_(f) is 0.50 in ethyl acetate, hexane, and acetic acid (35:14:1).Infrared absorptions are observed at 2980, 2910, 1750, 1450, 1360, 1340,1260, 1230, 1200, 1180, 1130, 1080, 1020, 990, and 870 cm.⁻¹.

D. A solution of 0.5 g. of the reaction product of part C in 25 ml of amixture of tetrahydrofuran, water, and acetic acid (1:3:6) is warmed to40° C. for 1 hr. The mixture is then poured into 100 ml. of cold brineand extracted three times with ethyl acetate and hexane (1:1). Thecombined organic extract is then washed with brine and ice coldsaturated sodium bicarbonate, dried over sodium sulfate, andconcentrated to yield 0.37 g. of an oil. This oil crude oil is thenchromatographed on 20 g. of silica gel, packed with 20 percent ethylacetate and hexane. Eluting with 40 percent ethyl acetate in hexane 0.27g. of PGD₂, 1,9-lactone is obtained as a light yellow oil. Silica gelR_(f) is 0.37 in 50 percent ethyl acetate in hexane. Infraredabsorptions are observed at 3460, 3000, 2960, 2920, 2860, 1740, 1580,1560, 1450, 1365, 1335, 1265, 1230, 1205, 1175, 1130, 1070, 1050, 1025,970, and 945 cm.⁻¹. Characteristic infrared absorptions are observed5.40, 4.0, and 0.9 δ. The mass spectrum shows parent peak at 406.2522and other peaks at 388, 378, 373, and 335.

Following the procedure of Example 9, but employing each of the variousPGD-type compounds described by formula I in place of PGD₂, there areobtained each of the various corresponding PGD-type, 1,9-lactones.

EXAMPLE 10 8β,12α -PGD₂ , 1,9-lactone

Refer to Chart B.

Following the procedure of Example 9, but employing 8β,12α-PGF₂α inplace of PGF₂α, there is obtained the title product.

Following the procedure of Example 10, but employing each of the various8β,12α-PGD-type compounds described by formula I in place of8β,12α-PGD₂, there is obtained each of the various corresponding8β,12α-PGD-type, 1,9-lactones.

EXAMPLE 11 9β-PGD₂ , 1,9-lactone

(Formula CLXXXVIII: Z₁, Y₁, M₁, L₁, and R₇ are as defined in Example 1).

Refer to Chart P.

A. A solution of 2.5 g. of 11β-PGF₂β methyl ester and 0.83 g. ofn-butylboronic acid in 75 ml. of ethylene chloride is refluxed. As 8 ml.aliquots of methylene chloride are removed by distillation, anadditional 8 ml. of methylene chloride is added to the reaction mixture.After cooling to ambient temperature, 15 ml. of dihydropyran in 0.2 g.of pyridine hydrochloride are added. This mixture is then allowed tostir for 12 hr. Thereafter the methylene chloride is evaporated underreduced pressure and a cooled mixture of 10 ml. of 30 percent hydrogenperoxide and 50 ml. of 1N sodium bicarbonate is added. The resultingmixture is then stirred for 45 min. Ethyl acetate is then added and thereaction mixture extracted several times with ethyl acetate. Thecombined organic extract is then washed with brine, dried over sodiumsulfate, and concentrated to an oil. This crude product is thenchromatographed on 200 g. of silica gel packed with 50 percent ethylacetate and Skellysolve B and eluted with 50 to 70 percent ethyl acetatein Skellysolve B. Thereupon, 1.8 g. of the methyl ester of the formulaCLXXXV compound is obtained as a colorless oil. Silica gel R_(f) is 0.33in 70 percent ethyl acetate in hexane. Infrared absorptions are observed3500, 2980, 2900, 1740, 1460, 1440, 1320, 1200, 1130, 1110, 1090, 1080,1020, 980, and 870 cm.⁻¹.

B. The methyl ester of part A (0.75 g.) in 30 ml. of 3N sodium hydroxideand methanol (1:1) is stirred for 90 min. Thereupon, the mixture ispoured into 50 ml. of ice-cold 2N sodium bisulfate and extracted twicewith ethyl acetate. The combined organic extracts are then washed withbrine, dried over sodium sulfate, and concentrated to yield 0.70 g. ofthe formula CLXXXV free acid. Silica gel R_(f) is 0.36 in the AIXsolvent system.

C. The reaction product of part B (1.0 g.), 0.90 g. oftriphenylphosphine, in 0.75 g. of 2,2'-dipyridyl disulfide in 15 ml. ofoxygen free benzene is allowed to stir at room temperature overnightunder a nitrogen atmosphere. Thereafter the mixture is diluted with 200ml. of oxygen free toluene and the solution is warmed to refluxtemperature for 30 hr. After cooling to room temperature, the solvent isevaporated under reduced pressure to yield a yellow oil. This crudeyellow oil is then chromatographed on 300 g. of silica gel, packed with15 percent ethyl acetate and hexane and eluted with 25 percent ethylacetate and hexane. Thereupon, 0.50 g. of the formula CLXXXVI lactone isobtained as an oil. Silica gel R_(f) is 0.25 and 0.32 in 25 percentethyl acetate in hexane. Infrared absorptions are observed at 3550,3000, 2920, 1750, 1460, 1420, 1350, 1310, 1260, 1235, 1200, 1140, 1115,1080, 1020, 985, and 870 cm.⁻¹.

D. A solution of 0.45 g. of the reaction product of part C and 25 ml. ofacetone is cooled to -25° C. Thereupon 0.50 ml. of Jones reagent isadded and after 45 min. at -25° to -20° C., 0.5 ml. of isopropanol isadded. After an additional 20 min. the mixture is then poured into 100ml. of ice-cold brine and extracted 3 times with ethyl acetate. Thecombined ethyl acetate extract is then washed twice with brine, driedover sodium sulfate, and concentrated to yield 0.43 g. of a formulaCLXXXVII compound as an oil. Silica gel R_(f) is 0.50 in 25 percentethyl acetate in hexane. A solution of this oil and 25 ml. of a mixtureof tetrahydrofuran, water, and acetic acid (1:3:6) is warmed to 40° C.for 90 min. Thereupon the solution is poured into 100 ml. of cold brineand extracted with 375 ml. of 30 percent ethyl acetate in hexane. Thecombined organic extract is then washed with brine, dried over sodiumsulfate, and concentrated to an oil. This crude oil is thenchromatographed on 40 g. of silica gel packed with 15 percent ethylacetate and hexane and diluted with 30 percent ethyl acetate and hexane.Thereupon 0.30 g. of purified product is obtained, which yields 165 mg.of colorless needle crystals. Melting point is 54°-55° C. Silica gelR_(f) is 0.25 in 30 percent ethyl acetate in hexane. Infraredabsorptions are observed at 3550, 3000, 2920, 1750, 1460, 1420, 1350,1320, 1270, 1230, 1150, 1075, 1070, 970, and 975 cm.⁻¹. NMR absorptionsare observed at 5.50, 5.10, and 4.15 δ. The mass spectrum shows parentpeak 334.2173.

Following the procedure of Example 11, but employing each of the various9β-PGD-type compounds described by formula I in place of 9β-PGD₂, thereare obtained each of the corresponding 9β-PGD₁ -type lactones.

EXAMPLE 12 8β,9β,12α-PGD₂, 1,9-lactone

(Formula CLXXIV: Z₁, Y₁, M₁, L₁, and R₇ are as defined in Example 1).

Refer to Chart N.

A. A solution of 0.60 g. of 8β,12α-PGF₂β, 1,9-lactone (Example 4) in 70ml. of dry acetone is cooled to -20° C. Thereupon, 2.8 ml. oftrimethylsilyldiethylamine is added. After 30 min., another 2.8 ml. oftrimethylsilydiethylamine is added. After 1.5 hr., the mixture is cooledto -70° C. and 150 ml. of cooled (-70° C.) diethyl ether is added. Thismixture is then poured into 100 ml. of ice-cold saturated sodiumbicarbonate and extracted 3 times with diethylether. The combinedetheral extracts are then washed with ice-cold saturated sodiumbicarbonate and brine, dried over magnesium sulfate, and concentrated toyield PGF₂β, 1,9-lactone, 15-trimethylsilyl ether (Formula CLXXII).

B. Employing the Collins Reagent the reaction product of part A of thisexample is oxidized to the corresponding formula CLXXIII compound.

C. Following the procedure of Example 9, part D, the reaction product ofpart B of this example is hydrolyzed to the title product.

Following the procedure of Example 12, but employing each of the various8β,9β,12α-PGD-type compounds described by formula I in place of8β,9β,12α-PGD₂, there are obtained each of the various8β,9β,12α-PGD-type, 1,9lactones.

EXAMPLE 13 PGF₂α, 1,11-lactone

(Formula CXLVIII: Z₁, Y₁, M₁, L₁, and R₇ are as defined in Example 1,and W₁ is ##STR97##

Refer to Chart K.

A. The first method of Chart K:

1. A stirred solution of one g. of PGD₂ (0° C.) in 25 ml. of anhydrouspyridine is treated with 3 g. of triphenylsilyl chloride and theresulting mixture then stirred for 6 hr. at 25° C. under a nitrogenatmosphere. This reaction mixture is then recooled to 0° C., dilutedwith 100 ml. of tetrahydrofuran (at 0° C.) and 40 ml. of water (at about40° C.). This mixture is then stirred 45 min. at 0° C. The resultingmixture is then poured into brine, acidified with 325 ml. of 1N sodiumbisulfate, and extracted with ethyl acetate in hexane (1:1). Thecombined extracts are then washed with brine, dried over sodium sulfate,and concentrated. The crude product, thusly obtained, is chromatographedon 300 g. of silica gel, packed with 10 percent ethyl acetate in hexaneand eluted with 10 to 20 percent ethyl acetate in hexane. Thereby, 2.15g. of the formula CXLII PGD₂, 9,15-bis-(triphenylsilyl ether) areobtained. Infrared absorptions are observed 3300, 3100, 2700, 1750,1720, 1600, 1490, 1430, 1370, 1240, 1115, 1040, 1000, 970, 740, 710, and700 cm.⁻¹. NMR absorptions are observed at 10.75. 7.9-7.2, 5.75-5.05,and 4.75-4.15 δ.

2. To a stirred solution of 4.10 g. of the reaction product of subpart(1) at 0° C. in 250 ml. of methanol is added 3.0 g. of sodiumborohydride in 100 mg. portions over a period of 15 min. After stirringan additional 15 min. at 0° C., the reaction mixture is then carefullypoured into a rapidly stirred mixture of ice, water, dilute sodiumbisulfate, and 50 percent ethyl acetate in hexane. After separation ofphases, the aqueous layer is extracted twice with ethyl acetate inhexane (1:1). The combined organic layer is then washed with brine,dried over sodium sulfate, and concentrated under reduced pressure. Thecrude product is then chromatographed on 450 g. of an acid washed silicagel. The column is packed with 10 percent ethyl acetate in hexane andeluted with 20 percent ethyl acetate in hexane. Thereupon, 2.90 g. ofthe formula CXLIV PGF₂α, 9.15-bis-(triphenylsilyl ether) is obtained.

3. A solution of 2.90 g. of the reaction product of subpart (2), 1.10 g.of 2,2'-diphyridylsulfide, and 1.31 g. of triphenylphosphine in 40 ml.of dry oxygen-free xylene is stirred at 25° C. under nitrogen atmospherefor 10 hr. The resulting mixture is then diluted with 800 ml. of xyleneand heated at reflux for 24 hr. After cooling, the xylene is removedunder reduced pressure and a dark red residue is then chromatographed on450 g. of neutral silica gel. The column is packed and eluted withbenzende. Thereupon, 2.20 g. of the formula CXLV PGF₂α, 1,11-lactone.9,15-bis(triphenylsilyl ether) is obtained. Infrared absorptions areobserved at 3100, 3050, 1730, 1590, 1480, 1440, 1420, 1325, 1260, 1220,1180, 1140, 1110, 1000, 970, 905, 900, 875, 740, 710, and 700 cm.⁻¹.

4. A stirred mixture of 2.20 g. of the reaction product of subpart (3),100 ml. of tetrahydrofuran, 80 ml. of water, and 20 ml. of 85 percentphosphoric acid is heated at 45° C. for 2 hr. After concentrating thereaction mixture under reduced pressure, water is added and the productis isolated by extraction with a mixture of ethyl acetate and hexane(3:1). The combined extracts are then washed with aqueous sodiumbicarbonate and brine, dried over magnesium sulfate, and evaporated.Crude product is then chromatographed on 125 g. of neutral silica gel,packed with 25 percent ethyl acetate in hexane, and eluted with 40 to 70percent ethyl acetate in hexane. Thereupon 615 mg. of title product isobtained. Infrared absorptions are observed at 3400, 3000, 2920, 2850,1730, 1710, 1450, 1355, 1335, 1270, 1225, 1185, 1145, 1100, 1085, 1005,965, and 705 cm.⁻¹. The mass spectrum shows parent peak 480.3073 andother peaks at 465, 409, 390, 375, 319, and 199.

B. The second method of Chart K:

1. Following the procedure of Example 9, part A, PGF₂α is transformed toPGF₂α, 15-(tetrahydropyranyl ether).

2. PGF₂α, 15-(tetrahydropyranyl ether), 2 g., in acetone (75 ml.) iscooled to -45° C. and thereafter treated with 1.2 ml. of the Jonesreagent. The resulting mixture is then stirred for 30 min. at -35 to-45° C. and thereafter treated with 0.5 ml. of isopropanol. Stirringcontinues an additional 15 min. The resulting mixture is then pouredinto a mixture of ice, water, and diethyl ether. This mixture is thenextracted with diethyl ether and combined ethereal extracts are thenwashed with brine and dried over sodium sulfate. After filtration,removal of solvent proceeds by rotary evaporation. Crude PGD₂,15-(tetrahydropyranyl ether), 1.8 g., thereby obtained, ischromatographed on 360 g. of acid washed silica gel eluting with 45percent ethyl acetate in hexane. 800 mg. of pure compound is therebyobtained.

3. Following the procedure of Example 13, part A, subpart A, thereaction product of subpart (2) of this part is silylated at C-9,preparing PGD₂, 15-(tetrahydropyranyl ether), 19-(triphenylsilyl ether).

4. Following the procedure of Example 13, part A, subpart 2, thereaction product of subpart 3 above is reduced and chromatographed,preparing a formula CXLIV compound.

5. Following the procedure of Example 13, part A, subpart 3, thereaction product of subpart 4 of this part is lactonized, preparingPGF₂α, 1,11-lactone, 15-(tetrahydropyranyl ether 9-triphenylsilylether).

6. The reaction product of subpart 5 of this part is then dissolved intetrahydrofuran (25 ml.) and treated with a solution oftetra-n-butylammonium fluoride in tetrahydrofuran. This reaction mixtureis then stirred at 65° C. for 2 hr. and thereafter cooled to ambienttemperature. The resulting product is then concentrated under reducedpressure, diluted with brine, and extracted with ethyl acetate. Theorganic extract is then washed with 2M aqueous potassium bisulfate andbrine and dried over magnesium sulfate. Concentration under reducedpressure yields PGF₂α, 1,11-lactone, 15(tetrahydropyranyl ether).

7. Following the procedure of Example 13, part A, subpart 4, thereaction product of subpart 6 of this part is transformed to the titleproduct by hydrolysis.

Following the procedure of Example 13, but employing each of the variousPGF.sub.α -type compounds described by formula I in place of PGF₂α,there is obtained each of the various corresponding PGF.sub.α -type,1,11-lactones.

EXAMPLE 14 8β,12α-PGF₂α, 1,11-lactone

(Formula CXXXVI: Z₁, Y₁, M₁, L₁, and R₇ are as defined in Example 1 andW₁ is ##STR98##

Refer to Charts J and K.

A. Following the procedure of Example 13, part A, employing 8β,12α-PGD₂,in place of PGD₂, there is obtained the title product.

B. The method of Chart J:

1. Following the procedure of Example 9, part A, 8β,12α-PGF₂α istransformed to 8β,12α-PGF₂α, 15-(tetrahydropyranyl ether), formulaCXXXII.

2. Following the procedure of Example 12, part A the reaction product ofsubpart 1 of this part is selectively silylated at C-9.

3. Following the procedure of Example 1, part A, the reaction product ofsubpart (2) of this part is 1,11-lactonized, preparing a formula CXXXIVcompound.

4. Following the procedure of Example 13, part B, subpart 6, thereaction product of subpart 3 or this part is selectively hydrolyzed atthe C-9 position, preparing 8β,12α-PGF₂α, 1,11-lactone15-(tetrahydropyranyl ether, a formula CXXXV compound.

5. Following the procedure of Example 13, part B, subpart 7, butemploying the reaction product of subpart 4 of this part the titleproduct is prepared.

Following the procedure of Example 14, but employing each of the various8β,12α-PGF.sub.α -type compound described by formula I in place of8β,12α-PGF₂α, there are obtained each of the various corresponding8β,12α-PGF₆₀ -type, 1,11-lactones.

EXAMPLE 15 PGE₂, 1,11-lactone

(Formula CXXII: Z₁, Y₁, M₁, L₁, and R₇ are as defined in Example 1).

Refer to Charts H or K.

A. Following the procedure of Example 9, part C, the reaction product ofExample 13, part B, subpart 6, is oxidized to the formula CXXI PGE-type,1,11-lactone.

B. Following the procedure of Example 13, part B, subpart 7, thereaction product of part A above is hydrolyzed to the title compound.

Following the procedure of Example 15, but employing each of the variousPGF₂α -type, 1,11-lactone, 15-(tetrahydropyranyl ethers) correspondingto each of the various PGF₂α, 1,11-lactones described following Example13, there are obtained each of the corresponding PGE₂, 1,11-lactones.

EXAMPLE 16 8β,12α-PGE₂, 1,11-lactone

(Formula CXXXVI: Z₁, Y₁, M₁, L₁, and R₇ are as defined in Example 1, andW₁ is ##STR99##

Refer to Charts J and K.

A. Following the procedure of Example 9, part C, the reaction product ofExample 14, part B, subpart 4, is transformed to 8β,12α-PGE₂,1,11-lactone, 15-(tetrahydropyranyl ether).

B. Following the procedure of Example 13, part B, subpart 7, thereaction product of part A above is transformed to the title product.

Following the procedure of Example 16, but employing each of the variousformula CXXXV PGF.sub.α -type, 1,11-lactone, 15-(tetrahydropyranylethers) in place of the reaction product of Example 14, part B, subpart4, there are obtained each of the various corresponding 8β,12α-PGE-type,1,11-lactones.

EXAMPLE 17 PGF₂β, 1,11-lactone

(Formula CXXIII: Z₁, Y₁, M₁, L₁, and R₇ are as defined in Example 1).

Refer to Charts H and K.

Following the procedure of Example 13, part B, subpart 4, but employingthe reaction product of Example 15, there is obtained the title product.

Following the procedure of Example 17, but employing each of the variousPGE-type, 1,11-lactones described following Example 15, in place ofPGE₂, 1,11-lactone, there are obtained each of the various PGF .sub.β-type, 1,11-lactones.

EXAMPLE 18 8β,12α-PGF₂β

(formula CXXXVI: Z₁, Y₁, M₁, L₁, and R₇ are as defined in Example 1, andW₁ is ##STR100##

Refer to Charts J and K.

Following the procedure of Example 13, part B, subpart 4, but employingthe reaction product of Example 16, there is prepared the title product.

Following the procedure of Example 18, but employing each of the various8β,12α-PGE-type, 1,11-lactones described following Example 16, in placeof 8β,12α-PGE₂, there is obtained each of the various corresponding8β,12α-PGF.sub.β -type, 1,11-lactones.

EXAMPLE 19 15-Methyl-PGF₂α, 1,11-lactone

(Formula CXCVI: Z₁, Y₁, L₁, and R₇ are as defined in Example 1, and R₅of the M₁₁ moiety is methyl).

Refer to Chart R.

A. 15-Methyl-PGF₂α is reacted with one equivalent of p-phenylbenzoylchloride. The reaction is monitored by silica gel thin layerchromatography and when the acylation at C-11 is complete, the reactionis terminated and the formula CXCII compound recovered.

B. Following the procedure of Example 13, part A, subpart 2,t-butyldimethylsilyl chloride is employed to transform the reactionproduct of part A above to the formula CXCIII9,15-bis-(t-butyldimethylsilyl) derivative.

C. The reaction product of part B is deacylated employing potassiumhydroxide in aqueous methanol. Pure formula CXCIV compound is therebyrecovered.

D. Following the procedure of Example 1A, the reaction product of part Cabove is 1,11-lactonized, forming a formula CXCV compound.

E. The formula CXCV compound is then hydrolyzed following the procedureof Example 13, part A, subpart 4, to the title product.

Following the procedure of Example 19, but employing each of the various15-methyl-PGF₂α -type compounds described by formula XLI in place of15-methyl-PGF₂α, there are obtained each of the various corresponding15-methyl-PGA-type, 1,11-lactones.

EXAMPLE 20 PGF₂α, 1,15-lactone

(the 8α,12β-isomer of Formula LXIV: Z₁, Y₁, R₅, L₁, and R₇ are asdefined in Example 1).

Refer to chart D.

A. A solution of 5.5 g. of PGF₂α and 1.79 g. of n-butylboronic acid in150 ml. of methylene chloride is heated at reflux for 15 min. Thereafterabout half the methylene chloride is removed by distillation atatmospheric pressure and additional methylene chloride added to restorethe volume to 150 ml. This distillation and replacement of methylenechloride is then repeated 3 times, after which all solvent is thenremoved under reduced pressure. Thereupon, crude formula LXII compoundis obtained.

B. The reaction product of pair A is then dissolved in 180 ml. ofanhydrous, oxygen-free xylene and treated with 5.128 g. of2,2'-dipyridyl disulfide, followed by addition of 6.27 g. oftriphenylphosphine. After 18 hr. at 25° C. under a nitrogen atmospherethe above solution is diluted with 300 ml. of oxygen free xylene andthereafter added dropwise over a 10 hr. period to 3.2 1. of vigorouslystirred refluxing xylene under a nitrogen atmosphere. After the additionis complete, 100 ml. of xylene is distilled off and the solution isheated at reflux for 24 hrs. The reaction mixture is then cooled and thexylene removed under reduced pressure, preparing a formula LXIIIcompound.

C. The reaction product of part B is then taken up in 500 ml. oftetrahydrofuran and treated with 10 ml. of 30 percent hydrogen peroxideand 100 ml. of saturated aqueous sodium bicarbonate. This mixture isthen stirred vigorously for 30 min. at 35° C. and then concentratedunder reduced pressure. The residue is then taken up in brine and ethylacetate and extracted thoroughly with ethyl acetate. The combinedorganic layer is then washed with 1N auqoues potassium bisulfate, water,aqueous sodium bicarbonate, and brine. After drying over sodium sulfate,removal of the solvent affords a viscous yellow oil which ischromatographed on 500 g. of acid washed silica gel. The column ispacked with 25 percent ethyl acetate and hexane and eluted with 50percent ethyl acetate and hexane. Title product is then crystallizedfrom 40 ml. of diethylether and hexane (1:1), affording 1.559 g. oftitle product. Melting point is 110°-111° C. Infrared absorptions areobserved at 3500, 3370, 3290, 3010, 1700, 1320, 1310, 1290, 1260, 1105,1080, 1055, 970, and 730 cm.⁻¹. NMR absorptions are observed 6.00-5.75,5.75-4.95, 4.30-3.85, and 2.65 δ. The mass spectrum shows parent peak480.3102 and other peaks at 465, 436, 409, 390, 380, 364, 238, and 217.

Following the procedure of Example 20, but employing each of the variousPGF.sub.α -type compounds described by formula 1 in place of PGF₂α,there are obtained each of the various corresponding PGF.sub.α -type,1,15-lactones.

EXAMPLE 21 8β,12α-PGF₂α, 1,15-lactones

Refer to Chart D.

Following the procedure of Example 20, but employing 8β,12α-PGF₂α inplace of PGF₂α, there is obtained the title product.

Following the procedure of Example 21, but employing each of the various8β,12α-PGF.sub.α -type compounds described by formula 1 in place of8β,12α-PGF₂α, there are obtained each of the various corresponding8β,12α-PGF.sub.α -type, 1,15-lactones.

EXAMPLE 22 PGE₂, 1,15-lactone

(Formula L: Z₁, R₈, Y₁, R₅, L₁, and R₇ are as defined in Example 1).

Refer to Chart C.

A. A solution of 1.7 g. of PGF₂α, 1,15-lactone (formula XLVIII) in 45ml. of anhydrous acetone is cooled under nitrogen to between -45° and-40° C. This solution is then treated with 4.5 ml. oftrimethylsilyldiethylamine. After addition is complete, the mixture isstirred at -45° to -40° C. for 2 hrs. This mixture is then cooled to-78° C., diluted with 150 ml. of precooled diethyl ether, and pouredinto an ice-brine mixture. After extraction with hexane, the combinedorganic layers are washed with aqueous sodium bicarbonate and brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. Thereby, 1.47 g. of a formula XLIX 11-trimethylsilyl compoundis obtained.

B. The Collins reagent is prepared by adding 2.45 g. of dry chromiumtrioxide to a cold (0° C.), stirred solution of 3.99 ml. of anhydrouspyridine in 120 ml. of methylene chloride. The resulting dark resolutionis then stirred at 25° C. for 1 hr., then cooled to 0° C. A solution ofthe reaction product of part A in 6 ml. of methylene chloride is thenadded in one portion to the rapidly stirred Collins reagent. The icebath is then removed and the reaction mixture is stirred an additional20 min. The mixture is then poured into a column containing 150 g. ofneutral silica gel. The column is then eluted with ethyl acetateyielding 1.357 g. of PGE₂, 1,15-lactone, 11-trimethylsilyl ether.

The reaction product of part B is then dissolved in 150 ml. of methanol,dilute with 60 ml. of aqueous 2.5 percent citric acid, and stirred at25° C. for 30 min. After removal of about half of the methanol byevaporation at reduced pressure, the remaining solution is diluted withbrine and extracted with ethyl acetate. The combined organic extractsare then washed with aqueous sodium bicarbonate and brine, dried oversodium sulfate, and concentrated.

The crude product is then crystallized from diethyl ether and hexane,yielding 6.08 g. of title product.

Following the procedure of Example 22, but employing each of the variousPGF.sub.α -type, 1,15-lactones described following Example 20, in placeof PGF₂α, 1,15-lactone, there are obtained each of the variouscorresponding PGF-type, 1,15-lactones.

Alternatively, the title compound of Example 22 or each of the variouscompounds described in the paragraph are obtained directly bylactonization of PGE₂ or a PGE-type compound by the procedure describedin Example 1, part A.

EXAMPLE 23 8β,12α-PGE₂, 1,15-lactone

(Formula LXIX: Z₁, Y₁, R₅, L₁, and R₇ are as defined in Example 1).

Refer to Chart D or E.

A. The method of Chart D:

1. Following the procedure of Example 12, part A,8β,12α-PGF₂α,1,15-lactone (Example 20) is selectively silylated at C-9.

2. Following the procedure of Example 9, part A, the reaction product ofsubpart 1 above is transformed to the corresponding11-(tetrahydropyranyl ether), a formula LXVI compound.

3. Following the procedure of Example 13, part B, subpart 6, thereaction product of subpart 2 above is selectively hydrolyzed at C-9(the silyl ether), preparing PGF₂α, 1,15-lactone, 11-(tetrahydropyranylether), a formula CLXVII compound.

4. Following the procedure of Example 9, part C, the reaction product ofsubpart 3 above is transformed to the corresponding PGE₂ -type,1,11-lactone (formula LXVIII).

5. Following the procedure of Example 9, part D, the reaction product ofsubpart 4 above is hydrolyzed to the title product.

B. Optionally, the title product is prepared by lactonization of8β,12α-PGE₂, following the procedure of Example 1, part A.

Following the procedure of Example 23, but employing each of the various8β,12α-PGF.sub.α -type 1,15-lactones described following Example 21 oreach of the various 8β,12α-PGE-type compounds described by formula XLI,respectively, in place of 8β,12α-PGF₂α, 1,15-lactone or 8β,12α-PGE₂,respectively, there are obtained each of the various 8β,12α-PGE-type,1,15-lactones.

EXAMPLE 24 PGF₂β, 1,15-lactone

(Formula LXXXV: Z₁, R₈, Y₁, R₅, L₁, and R₇ are as defined in Example 1).

Refer to Chart D or E.

Following the procedure of Example 13, part A, subpart 2, the reactionproduct of Example 22 is reduced and chromatographed to yield the titleproduct.

Following the procedure of Example 24, but employing each of the variousPGE-type 1,15-lactones described following Example 22, in place of PGE₂,1,15-lactone, there are obtained each of the various correspondingPGF.sub.β -type, 1,15-lactones.

EXAMPLE 25 8β,12α-PGF₂β, 1,15-lactone

(Formula LXXXVI: Z₁, R₈, Y₁, R₅, L₁, and R₇ are as defined in Example1).

Refer to Chart E.

Following the procedure described in Example 13, part A, subpart (2),8β,12α-PGE₂, 1,15-lactone is reduced and chromatographed to yield thetitle product.

Following the procedure of Example 25, but employing each of the various8β,12α-PGE-type, 1,15-lactone described following Example 23 in place of8β,12α-PGE₂, 1,15-lactone, there are obtained each of the variouscorresponding 8β,12α-PGF.sub.β -type, 1,15-lactones.

EXAMPLE 26 11-Deoxy-PGE₂, 1,15-lactone

(Formula CV: Z₁, Y₁, M₁, L₁, and R₇ are as defined in Example 1).

Refer to Chart G.

Following the procedure of Example 1, part A, 11-deoxy-PGE₂ islactonized to form the title product.

Following the procedure of Example 26, but employing each of the various11-deoxy-PGE-type compounds described by formula I in place of11-deoxy-PGE₂, there are obtained each of the various corresponding11-deoxy-PGE-type, 1,15-lactones.

EXAMPLE 27 11-Deoxy-8β, 12α-PGE₂.

Refer to Chart G.

Following the procedure of Example 1, part A, 11-deoxy-8β,12α-PGE₂ islactonized to the title product.

Following the procedure of Example 27, but employing each of the various11-deoxy-8β,12α-PGE-type compounds described by formula I in place of11-deoxy-8β,12α-PGE₂, there are obtained each of the variouscorresponding 8β,12α-11-deoxy-PGE-type, 1,15-lactones.

EXAMPLE 28 11-Deoxy-PGF₂α or 11-deoxy-PGF₂β

(formula LXXXV: Z₁, Y₁, R₅, L₁, and R₇ are as defined in Example 1, andR₈ is hydrogen).

Refer to Chart E.

Following the procedure of Example 13, part A, subpart 2, 11-deoxy-PGE₂,1,15-lactone is reduced and chromatographed yielding the title products.

Following the procedure of Example 27, but employing each of the various11-deoxy-PGE-type, 1,15-lactones described following Example 26 in placeof 11-deoxy-PGE₂, 1,15-lactone, there are obtained each of the variouscorresponding 11-deoxy-PGE-type, 1,15-lactones.

EXAMPLE 29 11-deoxy-8β,12α-PGF₂α or 11-deoxy-8β,12α-PGF₂β

(formula LXXXVI: Z₁, Y₁, R₅, L₁, and R₇ are as defined in Example 1 andR₈ is hydrogen).

Refer to Chart E.

Following the procedure of Example 13, part A, subpart 2,11-deoxy-8β,12α-PGE₂ is reduced and chromatographed yielding the titleproducts.

Following the procedure of Example 29, but employing each of the various8β,12α-PGE-type, 1,15-lactones described following Example 27, in placeof 8β,12α-PGE₂, 1,15-lactone there are obtained each of the variouscorresponding PGE-type, 1,15-lactones.

EXAMPLE 30 PGA₂, 1,15-lactone

(Formula XCII: Z₁, Y₁, R₅, L₁, and R₇ are as defined in Example 1).

Refer to Chart F or G.

A. The method of Chart F:

1. PGE₂, 1,15-lactone is dissolved in pyridine, combined with oneequivalent of acetic anhydride and allowed to stand at 25° C. for 3 hrs.Thereupon, PGE₂, 1,15-lactone, 11-acetate is prepared. The reactionmixture is then cooled in an ice bath treated dropwise over 15 min. with20 ml. of methanol. The ice bath is then allowed to melt and thetemperature allowed to rise to ambient temperature. After an additional18 hrs., the reaction mixture is then poured into a mixture of ice,diethyl ether, water, and 70 ml. of 2N aqueous potassium bisulfate. Thismixture is then extracted thoroughly with diethyl ether and etheralextract washed with water, aqueous sodium bicarbonate and brine. Thismixture is then dried over anhydrous sodium sulfate and concentratedunder reduced pressure.

2. The crude product of subpart (1) above is then chromatographed on 100g. of neutral silica gel. The column is packed and diluted with 15percent ethyl acetate and hexane. Thereupon 46 mg. of title product areobtained. This material crystallizes on standing and recrystallizationis effected from diethyl ether and hexane. The melting point is60°-61.5° C. NMR absorptions are observed at 7.50-7.33 and 6.27 to 6.06.The mass spectrum shows parent peak 316.2074 and other peaks 298, 288,259, 229, and 198. Infrared absorptions are observed at 3010, 1715,1705, 1580, 1355, 1345, 1325, 1245, 1170, 1145, 1140, 1035, and 970cm.⁻¹.

B. Alternatively, the title product is prepared from PGA₂ by directlactonization according to Example 1, part A.

Following the procedure of Example 30, but employing each of the variousPGE-type, 1,15-lactones described following Example 26 or PGA-typecompounds described by formula LXI, respectively, there are obtainedeach of the various corresponding PGA-type, 1,15-lactones.

EXAMPLE 31 8β,12α-PGA₂, 1,15-lactone

(Formula XCIV: Z₁, Y₁, R₅, L₁, and R₇ are as defined in Example 1).

Refer to Chart F or G.

Following the procedure of Example 30, part A, or Example 30, part B,8β,12α-PGE₂, 1,15-lactone or 8β,12α-PGA₂, respectively, is transformedto the title product.

Following the procedure of Example 31, but employing each of the various8β,12α-PGE-type, 1,15-lactones described following Example 27 orPGA-type compounds described by formula I, in place of 8β,12α-PGE₂,1,15-lactone or 8β,12α-PGA₂, respectively, there are obtained each ofthe various corresponding 8β,12α-PGA-type, 1,15-lactones.

EXAMPLE 32 PGB₂, 1,15-lactone

(Formula CVI: Z₁, Y₁, R₅, L₁, and R₇ are as defined in Example 1).

Refer to Chart G.

PGB₂ (0.334 g.), 5 ml. of dry, oxygen-free xylene, 0.393 g. oftriphenylphosphine, and 0.33 g. of 2,2'-dipyridyl sulfide are stirred atroom temperature under a nitrogen atmosphere for 6 hrs. The resultingmixture is then diluted with 250 ml. of dry, oxygen-free xylene, and thesolution heated at reflux for 16 hr. The resulting mixture is thenconcentrated under reduced pressure at a bath temperature of 40° C. toremove the xylene. The residue is then chromatographed on a dry packcolumn of 100 g. of silica gel and 20 ml. of diethyl ether. The columnis then eluted with 60 percent diethyl ether and hexane. Thereupon 200mg. of PGB₂, 1,15-lactone are obtained. Silica gel R_(f) is 0.37 indiethyl ether and hexane (1:1). The mass spectrum shows parent peak316.2021 and other peaks at 298, 288, 269, and 217. Characteristic NMRabsorptions are observed at 5.97-6.80, 5.07-5.70, and 2.83-3.12 δ. UVabsorption is observed at 277 mμ (ε = 16,800).

Following the procedure of Example 32, but employing each of the variousPGB-type compounds described by formula XLI in place of PGB₂, there areobtained each of the various corresponding PGB-type, 1,15-lactones.

EXAMPLE 33 PGD₂, 1,15-lactone.

Refer to Chart C.

A. Method employing PGF₂α, 1,15-lactone as starting material:

1. To a stirred solution at 0° C. of 1.0 g. of PGF₂α, 1,15-lactone and 3ml. of anhydrous dimethylformamide is added at 0° C. a solution of 474mg. of t-butyldimethylsilyl chloride and 428 mg. of imidazole in 3 ml.of dimethylformamide. The resulting mixture is then stirred for 1 hr. at0° C. under nitrogen, then poured into brine, and extracted with hexane.The combined organic layer is then washed successively with water, coldaqueous sodium bisulfate, water, aqueous sodium bicarbonate, and brine.The organic layer is then dried over sodium sulfate and concentratedunder reduced pressure. The crude product is then chromatographed on 140g. of neutral silica gel. The column is packed with 5 percent ethylacetate and hexane and diluted with 20 percent ethyl acetate and hexane.Thereupon, 1.10 g. of PGF₂α,1,15-lactone, 11-(t-butyldimethylsilylether) are obtained. Infrared absorptions are observed at 3500, 1730,1460, 1240, 1125, 1110, 1040, 1005, 975, 880, 840, and 780 cm.⁻¹. NMRabsorptions are observed at 5.90-4.95, 4.25-3.75, 3.70, and 0.85 δ.

2. A solution of 1.05 g. of the reaction product of part (1) above, 5ml. of freshly distilled dihydropyran, and 50 mg. of pyridinehydrochloride in 25 ml. of anhydrous methlene chloride are stirred undera nitrogen atmosphere at 25° C. for 18 hrs. The reaction mixture is thenpoured into a mixture of ice, sodium bicarbonate, and water, andextracted thoroughly with hexane. The organic extracts are then washedwith brine, dried over sodium sulfate, and concentrated under reducedpressure to yield a crude product (1.4 g.) which is chromatographed on140 of neutral silica gel. The column is packed with 5 percent ethylacetate and hexane and diluted with 10 percent ethyl acetate in hexane.Thereupon 1.16 g. of PGF₂α, 1,15-lactone, 9-(tetrahydropyranyl ether),11-(t-butyldimethylsilyl ether) are obtained. Infrared absorptions areobserved at 1740, 1460, 1350, 1240, 1140, 1120, 1040, 1020, 990, 975,860, 840, and 780 cm.⁻¹. Infrared absorptions are observed at 5.95-5.0,4.75-4.50, 4.30-3.25, and 0.88 δ.

3. To a solution of 1.17 g. of the reaction product of subpart (2) abovein 5 ml. anhydrous tetrahydrofuran at 25° C. is added under a nitrogenatmosphere 22 ml. of a 0.3M solution of tetra-n-butyl ammonium fluoridein tetrahydrofuran. The reaction mixture is then stirred for 30 min. at25° C., then poured into a mixture of ice, water, sodium bicarbonate,and hexane. The resulting mixture is then extracted thoroughly withhexane and the organic extracts are then washed with brine, dried oversodium sulfate, and evaporated. The crude product (1.1 g.) is usedwithout further purification. A 75 mg. sample of this crude product,however, is chromatographed on 15 g. of neutral silica gel, packed with10 percent ethyl acetate in hexane and eluted with 10 percent ethylacetate in hexane. Accordingly, 16 mg. of pure PGF₂α, 1,15-lactone,9-(tetrahydropyranyl ether) are obtained. Infrared absorptions areobserved 3500, 1730, 1440, 1340, 1240, 1200, 1160, 1140, 1120, 1080,1040, 1020, 990, 970, 920, 870, 815, and 735 cm.⁻¹. NMR absorptions areobserved at 6.0-5.0, 5.75-5.0, 4.35-3.30, and 2.35 δ.

4. A solution of 920 mg. of the reaction product of subpart (3) above in30 ml. of acetone is cooled to between -20° and -30° C. This cooledmixture is then treated dropwise with 0.8 ml. of the Jones reagent.After 75 min. at -20° to -30° C., 0.5 ml. of isopropyl alcohol is addedto destroy excess oxidizing reagent. After an additional 10 min. ofstirring at -25° C., the mixture is diluted with 400 ml. of water andextracted thoroughly with a mixture of hexane and ethyl acetate (4:1).The combined organic extracts are then washed successively with water,ice cold aqueous sodium bisulfate, water, aqueous sodium bicarbonate,and brine. The organic extract is then dried over sodium sulfate andconcentrated under reduced pressure. This crude (900 mg.) is thenchromatographed on 140 g. of neutral silica gel, packed with 5 percentethyl acetate in hexane and eluted with 20 percent ethyl acetate inhexane. Thereupon, 750 mg. of PGD₂, 1,15-lactone, 9-(tetrahydropyranylether) are obtained. Infrared absorptions are observed at 1745, 1460,1440, 1370, 1340, 1240, 1200, 1160, 1140, 1120, 1080, 1040, 1020, 995,980, 920, 870, 815, and 735 cm.⁻¹. NMR absorptions are observed at5.90-5.0 and 4.80-3.40 δ.

5. A mixture of 700 mg. of the reaction product of subpart (4) above, 33ml. of tetrahydrofuran, 33 ml. of water, and 66 ml. of acetic acid isheated at 40° C. for 3 hrs. The resulting mixture is then cooled tobelow room temperature, poured into a mixture of brine and water (1:1),and extracted thoroughly with a mixture of ethyl acetate and hexane(1:1). The combined organic extracts are then washed with aqueous sodiumbicarbonate and brine, dried over sodium sulfate and evaporated. Crudeproduct is then crystallized from diethyl ether and hexane mixturesyielding 243 mg. of pure title product. Melting point 93°-94° C.Infrared absorptions are observed at 3470, 3020, 1735, 1725, 1245, 1225,1160, 1145, 1045, 1025, 960, and 917 cm.⁻¹. NMR absorptions are observedat 5.95-5.35, 5.4-4.95, 4.65-4.30, and 2.45 δ. The mass spectrum showsparent peak at 406.2574 and other peaks at 391, 388, 373, 335, 316, 290,and 279.

B. Employing PGF₂α as starting material:

1. PGF₂α is selectively silylated at C-11 and C-15, preparing theformual XLII compound; etherified at C-9, preparing the formula XLVcompound; and selectively desilylated at C-11 and C-15 forming a formulaXLVI compound; following the procedures described in Example 33, part A,subparts (1), (2), and (3).

2. The reaction product of subpart (1) above is then 1,15-lactonizedfollowing the procedure of Example 1, part A, preparing a formula XLVIIcompound, PGF₂α, 1,15-lactone, 9-(tetrahydropyranyl ether).

3. The reaction product of subpart (2) above is oxidized to a ketone atC-11 and hydrolyzed at C-9, following the procedure of Example 33, partA, subparts (4) and (5), thereby preparing the title product.

Following the procedure of Example 33, part A, or Example 33, part B,but employing each of the various PGF.sub.α -type, 1,15-lactonesdescribed following Example 20, or PGF.sub.α -type compounds describedby formula I, respectively, in place of PGF₂α, 1,15-lactone or PGF₂α,respectively, there are obtained each of the various correspondingPGD-type, 1,15-lactones.

EXAMPLE 34 8β,12α-PGD₂, 1,15-lactone

(Formula LXXIII: Z₁, Y₁, R₅, L₁, and R₇ are as defined in Example 1).

Refer to Chart D.

8β,12α-PGF₂α, 1,15-lactone (Example 21) is selectively silylated at C-9,following the procedure of Example 12, part A, preparing a formula LXVcompound.

B. This formula LXV compound is then oxidized at C-11, following theprocedure of Example 12, part B, thereby preparing a formula LXXIIPGD-type 9-silyl ether.

C. Following the procedure of Example 12, part C, the reaction productof part B above is hydrolyzed, thereby preparing the title product.

Following the procedure of Example 34, but employing each of the various8β,12α-PGF.sub.α -type, 1,15-lactones described following Example 21 inplace of 8β,12α-PGF₂α, 1,15-lactone, there are obtained each of thevarious corresponding 8β,12α-PGF.sub.α -type, 1,15-lactones.

EXAMPLE 35 9β-PGD₂, 1,15-lactone

(Formula CLVII: Z₁, Y₁, R₅, L₁, and R₇ are as defined in Example 1).

Refer to Chart L.

A. Following the procedure of Example 12, part A, PGE₂,1,15-1,15-lactone silylated at C-11, preparing a formula CLII compound.

B. Following the procedure of Example 13, part B, subpart 4, thereaction product of part A above is reduced at C-9 and chromatographedyielding a 9β-hydroxy formula CLIII compound.

Following the procedure of Example 33, part A, subparts (2)-(5), thereaction product of part B above is etherified at C-9, thereby preparingthe formula CLIV compound; selectively hydrolyzed at C-11 (silylremoval), preparing a formula CLV compound; oxidized at C-11, preparinga formula CLVI compound; and hydrolyzed at C-9, thereby prepreparing thetitle product.

Following the procedure of Example 35, but employing each of the variousPGE-type, 1,15-lactones described following Example 22, in place ofPGE₂, 1,15-lactone, there are obtained each of the various corresponding9β-PGD-type, 1,15-lactones.

EXAMPLE 36 8β,9β,12α-PGD₂,1,15-lactones

Refer to Chart L.

Following the procedure of Example 35, but employing 8β,12α-PGE₂,1,15-lactone (Example 23) in place of PGE₂, 1,15-lactone, there isobtained the title product.

Following the procedure of Example 36, but employing each of the various8β,12α-PGE-type, 1,15-lactones described following Example 23 in placeof 8β,12α-PGE₂, 1,15-lactone, there are obtained each of the variouscorresponding 8β,9β,12α-PGD-type, 1,15-lactones.

EXAMPLE 37 9-Deoxy-9,10-didehydro-PGD₂, 1,15-lactone

(Formula XCVI: Z₁, Y₁, R₅, L₁, and R₇ are as defined in Example 1).

Refer to Chart F.

Following the procedure of Example 30, PGD₂, 1,15-lactone is dehydrated,yielding the title compound.

Following the procedure of Example 37, but employing each of the variousPGD-type, 1,15-lactones described following Example 33, or each of thevarious 9,10-didehydro-9-deoxy-PGD-type compounds described by formulaI, there are prepared each of the various corresponding9-deoxy-9,10-didehydro-PGD-type, 1,15-lactones.

EXAMPLE 38 9-Deoxy-9,10-didehydro-8β,12α-PGD₂

(formula XCVIII: Z₁, Y₁, R₅, L₁, and R₇ are as defined in Example 1).

Refer to Chart F.

Following the procedure of Example 30 8β,12α-PGD₂, 1,15-lactone isdehydrated, preparing the title compound.

Following the procedure of Example 38, but employing each of the various8β,12α-PGD-type compounds described following Example 34 or9-deoxy-9,10-didehydro-8β,12α-PGD-type compounds described by formulaXLI, there are prepared each of the various corresponding9-deoxy-9,10-didehydro-8β,12α-PGE-type, 1,15-lactones.

EXAMPLE 39 9-deoxy-PGD₂, 1,15-lactone

(Formula CVI: Z₁, Y₁, R₅, L₁, and R₇ are as defined in Example 1).

Refer to Chart O.

A. To a stirred solution of 9-deoxy-9,10-didehydro-PGD₂, 1,15-lactonedissolved in methanol at -25° C. under a nitrogen atmosphere, there isadded a solution of sodium borohydride in water and methanol. Thismixture is then stirred at -20° C. for 20 min. and thereafter a smallquantity of acetic acid is added cautiously. The mixture is concentratedand an additional water is added and the pH of the mixture is thereafteradjusted to 3 by addition of citric acid. The resulting mixture is thenextracted with dichloromethane and the combined organic extracts arewashed with water and brine, dried, and concentrated to yield thecorresponding formula CLXXVII 9-deoxy-PGF₂α, 1,15-lactone.

B. To a solution of the reaction product of part A dissolved in acetoneat -20° C., there is added dropwise with stirring over one min. theJones reagent. This resulting mixture is then stirred at -20° C. for anadditional 20 min. and thereafter a small quantity of isopropanol isadded. This mixture is then stirred for about 10 min. at -20° C.Thereafter the mixture is diluted with water and extracted with diethylether. Combined organic extracts are washed, dried, and concentrated.The resulting residue is then chromatographed on silica gel, yieldingpure title product.

Following the procedure of Example 39, but employing each of the various9-deoxy-9,10-didehydro-PGD-type, 1,15-lactones described by formulaCLXXVI in place of 9-deoxy-9,10-didehydro-PGD₂, 1,15-lactone there areobtained each of the various corresponding 9-deoxy-PGD-type,1,15-lactones.

EXAMPLE 40 9-deoxy-8β,12α-PGD₂, 1,15-lactone

(Formula CVI: Z₁, Y₁, R₅, L₁, R₇ are as defined in Example 1).

Refer to Chart G.

Following the procedure of Example 39,9-deoxy-9,10-didehydro-8β,12α-PGD₂, 1,15-lactone is thereby transformedto the title product.

Following the procedure of Example 40, but employing each of the various9-deoxy-9,10-didehydro-8β,12α-PGD-type, 1,15-lactones describedfollowing Example 39, there are obtained each of the variouscorresponding 9-deoxy-8β,12α-PGD₂ -type, 1,15-lactones.

EXAMPLE 41 cis-4,5-Didehydro-PGF₁α, 1,9-lactones

(Formula XXII: Z₁ is cis--CH₂ --CH═CH--(CH₂)₂ -, R₈, Y₁, M₁, L₁, and R₇are as defined in Example 1).

Refer to Chart A.

cis-4,5-Didehydro-PGF₁α (130 mg.) is lactonized following the procedureof Example 1, part A, yielding 40 mg. of title product. Melting point is83°-85° C. NMR absorptions are observed at 7.80-7.42, 5.68-5.08,4.28-3.52, and 3.33-0.65 δ.

EXAMPLE 42 15-epi-15-Metyl-13,14-dihydro-PGF₂α, 1,9-lactone or15-epi-15-methyl-13,14-dihydro-PGF₁α, 1,9-lactone

15-Methyl-PGF₂α, 1,9-lactone (Example 43, 1.17 g.), 234 ml. of ethylacetate, and 0.7 g. of 5 percent palladiumon-charcoal catalyst arecombined and stirred at 0° C. under a hydrogen atmosphere. After about 2hrs. hydrogen uptake is terminated, and the filtrate is evaporated andazeotrope with benzene to yield 1.189 g. of an oil. This oil is thenchromatographed on silica gel, eluting with 75 percent ethyl acetate inhexane. Thereupon, 0.2 g. of 15-epi-15-methyl-13,14-didehydro-PGF₂α,1,9-lactone, and 0.58 g. of 15-epi-15-methyl-13,14-dihydro-PGF₂α,1,9-lactone are obtained. For 15-epi-15-methyl-13,14-didehydro-PGF₁α,1,9-lactone, lactone, the mass spectrum shows a parent peak at 483.3303and another peak at 488. NMR absorptions are observed at 5.5-5.03, 4.25-3.60, and 3.00-0.60 δ.

EXAMPLE 43 15-Epi-15-Methyl-PGF₂α, 1,9-lactone

(Formula XXII: Z₁, R₈, Y₁, L₁, and R₇ are as defined in Example 1, andM₁ is ##STR101##

Refer to chart A.

15-Epi-15-Methyl-PGF₂α (1.01 g.) 5 ml. of benzene, 1.04 g. oftriphenylphosphine, and 0.87 g. of 2,2'-dipyridylsulfide are reactedfollowing the procedure of Example 1, part A. Pure product is recoveredfrom the reaction mixture employing high pressure liquid chromatography,eluting with 100 percent ethyl acetate. Thereby, 1.08 g. of product isobtained which is rechromatographed on 125 g. of silica gel, elutingwith diethyl ether. Chromatography is continued until 380 mg. of pureproduct is obtained. Silica gel R_(f) is 0.3 in 75 percent ethyl acetatein Skellysolve B. The mass spectrum shows a base peak at 494.3234 andother peaks at 479, 423, 404, 389, 333, 186, and 143. Infraredabsorptions are observed at 3420, 2960, 2940, 2860, 1740, 1715, 1450,1370, 1350, 1225, 1180, 1145, 1125, 1085, 1045, 1030, and 970 cm.⁻¹.

Example 44 15-epi-15-methyl-PGF₂β, 1,9-lactone

(Formula XXII: Z₁,R₈,M₁, L₁, and R₇ are as defined in Example 43).

Refer to Chart A.

15-epi-15-Methyl-PGF₂α (0.62 g.), 0.67 g. of triphenylphosphine, in 0.65g. of 2,2'-dipyridylsulfide is lactonized following the procedure ofExample 1, part A. A resulting yellow colored solution is thenevaporated at 45° C. to yield 2.3 g. of a yellowish-brown oil. This oilis then dissolved in ethyl acetate, washed with 2M sodium bisulfate,saturated sodium bicarbonate, and brine and dried over sodium sulfate toyield 1.8 g. of a light brown oil. This oil is then chromatographed on200 g. of silica gel packed in 50 percent ethyl acetate and SkellysolveB, eluting with ethyl acetate. Chromatography is repeated employingsilica gel packed in 25 percent ethyl acetate in hexane, eluting with 50percent ethyl acetate in hexane, yielding 130 mg. of title product.Silica gel R_(f) is 0.42 in 75 percent ethyl acetate in Skellysolve B.The mass spectrum shows parent peak at 494.3249. (TMS derivative

EXAMPLE 45 15-Methyl-PGF₂α, 1,9-lactone

(Formula XXII: Z₁, R₈, Y₁, L₁, and R₇ are as defined in Example 43 andM₁ is ##STR102##

Refer to Chart A.

A solution of 15-methyl-PGF₂α (185 mg.) in 2.5 ml. of an anhydrous,oxygen-free xylene containing 2,2'-dipyridyl disulfide (165 mg.) andtriphenylphosphine (196 mg.) is stirred under nitrogen for 2.5 hr. at25° C. The mixture is diluted with 150 ml. of xylene and heated atreflux for 3 hr. TLC (80 percent EtOAc/hexane) shows essentially asingle, less polar product. The xylene is removed by evaporation atreduced pressure to afford a residue which is diluted withice/water/sodium bicarbonate and ethyl acetate and extracted thoroughlywith ethyl acetate. The ethyl acetate extract is washed with brine,dired over anhydrous sodium sulfate and concentrated to afford a residueof (15S)-15-methyl PGF₂α, 1,9-lactone. The residue is purified bychromatography on 50 g. of neutral silica packed with 10 percentacetone/methylene chloride and eluted (5 ml. fractions) with 200 ml. of10percent acetone/methylene chloride, 1500 ml. of 20 percentacetone/methylene chloride and 1000 ml. of 35 percent acetone/methylenechloride.

Those fractions containing homogeneous product by TLC assay (fractions135-229) are combined to yield pure 15-methyl-PGF₂α, 1,9-lactone.

The product exhibits infrared peaks at 3400, 3000, 2960, 2920, 2860,1740, 1715, 1450, 1370, 1350, 1265, 1225, 1205, 1180, 1145, 1125, 1085,1030, 970, 935, 905, and 715 cm⁻¹ and the mass spectrum shows peaks atm/e 350 (M+), 332 (M-18), 314, 303, 288, 261, 243.

EXAMPLE 46 15-Methyl-17-phenyl-18,19,20-trinor-PGF₂α, 1,9-lactone

(Formula XXII: Z₁, R₈, Y₁, M₁, and L₁ are as defined in Example 45 andR₇ is ##STR103##

Refer to Chart A.

A solution of 15-methyl-17-phenyl-18,19,20-trinor-PGF₂α (474 mg.) in 10ml. of of benzene is treated with triphenylphosphine (464 mg.) and2,2'-dipyridyl disulfide (390 mg.). The resulting yellow solution isstirred for 2 hrs. at 25° C. under nitrogen, then diluted with 250 ml.of anhydrous, oxygen-free benzene and heated at reflux for 24 hrs. Thebenzene is removed in vacuo to afford a residue which is chromatographedon 60 g. of neutral silica packed with 10 percent acetone/methylenechloride and eluted with 300 ml. of 10 percent acetone/methylenechloride followed by 1000 ml. of 20 percent acetone/methylene chloride(fraction size approx. 7 ml.).

Those fractions containing homogeneous product by TLC analysis(fractions 80-95) are combined, affording pure

15-methyl-17-phenyl-18,19,20-trinor-PGF₂α, 1,9-lactone with infraredpeaks at 3400, 3060, 2960, 2940, 2860, 1735, 1710, 1605, 1495, 1450,1365, 1345, 1265, 1225, 1180, 1145, 1115, 1085, 1030, 975, 750, 720 and700 cm.⁻¹ and NMR peaks at 7.27 (pehnyl; singlet; 5H), 5.8-5.1 (vinyland C-9H; multiplet; 5H), 4.30-3.75 (CHOH; multiplet; 1H) and 1.40 ppm(15-CH₃ ; singlet; 3H) and mass spectrum peaks at M+ 528.3112 (calc'd.for C₃₀ H₄₈ Si₂ O₄ : 528.3091); as well as m/e 513, 438, 423, 333, 91.

EXAMPLE 47 2,2-Difluoro-15-methyl-PGF₂α, 1,9-lactone

(Formula XXII: Z₁ is cis--CH═CH--(CH₂)₂ --CF₂ --, R₈, Y₁, M₁, L₁, and R₇are as defined in Example 45).

Refer to Chart A.

A solution of 2,2-difluoro-P15-methyl-PGF₂α methyl ester (150 mg.) in 5ml. of methanol at 0° is treated with 4 ml. of 3N aqueous potassiumhydroxide and stirred under nitrogen at 0° for 30 min. The reactionmixture is acidified with cold aqueous potassium bisulfate and extractedthoroughly with ethyl acetate. The extract is washed with brine, driedover sodium sulfate and concentrated to afford a residue of2,2-difluoro-15-methyl-PGF₂α.

The residue is immediately dissolved in 10 ml. of anhydrous, oxygen-freebenzene, treated with triphenylphospine (141 mg.) and 2,2'-dipyridyldisulfide (118 mg.), and stirred at room temperature for 20 min. whenTLC (AIX) analysis indicates that, in addition to the pyridinethiolester formation, lactonization had already occurred as well. The solventis removed under vacuum to yield a residue containing2,2-difluoro-15-methyl-PGF₂α, 1,9-lactone.

The residue is purified by chromatography on 60 g. of neutral silicapacked with 30 percent aceton/methylene chloride and eluted with 40percent acetone/methylene chloride (approx. 6 ml. fractions).

Those fractions which are homogeneous by TLC analysis (fractions 49-56)are combined to afford pure (15S) 2,2-difluoro-15-methyl-PGF₂α,1,9-lactone with NMR preaks

at 5.90-5.10 (vinyl and C-9H; multiplet, 5H), 4.10-3.65 (CHOH;multiplet; 1H) and 1.26 ppm (CH₃ ; signlet; 3H).

The mass spectrum establishes molecular weight as m/e 530.3078 for thetrimethylsily ether (calc'd. for C₂₇ H₄₈ Si₂ ORF₂ : 530.3059).

EXAMPLE 48 cis-4,5-Didehydro-PGF₁α, 1,15-lactone

(the 8β,12α-isomer of Formula LXIV: Z₁ is cis--CH₂ --CH═CH--(CH₂)₂ --,R₈, Y₁, R₅, L₁, and R₇ are as defined in Example 1).

Refer to Chart A.

A. cis-4,5-Didehydro-PGF₁α (200 mg.) of n-butylboronic acid in 10 ml. ofdichloromethane are reacted according to the procedure of Example 20,part A yielding 340 mg. of an oil.

B. The oil is then dissolved in 6.5 ml. of oxygen-free xylene and 190mg. of 2,2'-dipyridyl sulfide followed by addition of 223 mg. oftriphenylphosphine. Thereafter, the reaction proceeds as is described inExample 20, parts B and C. Chromatography yields 80 mg. of pure product.Silica gel R_(f) is 0.35 and ethyl acetate. The mass spectrum shows basepeak at 480.3069 and other peaks at 480, 465, 390, 364, 300, and 217.NMR absorptions are observed at 6.25-4.83, 4.30-3.80, and 2.90-0.65 δ.

EXAMPLE 49 13,14-Didehydro-PGF₁α, 1,15-lactone

(the 8β,12α-isomer of Formula LXIV: Z₁ is -- (CH₂)₅ --, Y₁ is--C.tbd.C--, R₈, M₁, L₁, and R₇ are as defined in Example 1).

Refer to Chart D.

Following the procedure of Example 48, 880 mg. of 13,14-Didehydro-PGF₁αis transformed to 80 mg. of the title product. Melting point is 75°-76°C. Infrared absorptions are observed at 3500, 2950, 2250, 1740, 1455,1370, 1235, 1040, 735 cm.⁻¹. NMR absorptions are observed at 5.58-5.20,4.40-3.90, 3.53-0.60 δ.

EXAMPLE 51 13,14-Didehydro-PGF₂α, 1,15-lactone

(the 8α,12β-isomer of Formula LXIV: Y₁ is --C.tbd.C--, Z₁, R₅, L₁, andR₇ are as defined in Example 1).

Refer to Chart D.

Following the procedure of Example 48, but employing 240 mg. of13,14-didehydro-PGF₂α, there is obtained 80 mg. of title product. R_(f)is 0.4 in diethyl ether. Infrared absorptions are observed at 3300,2940, 1735, 1330, 1240, 1140, 1115, 1100, and 1040 cm.⁻¹. NMRabsorptions are observed at 5.75-5.22, 4.38-4.03, and 2.93-0.72 δ.

EXAMPLE 51 17-Phenyl-18,19,20-trinor-PGF₂α, 1,15-lactone

(the 8α,12β-isomer of Formula LXIV: Z₁, Y₁, R₅, and L₁ are as defined inExample 1, and R₇ is ##STR104##

Refer to Chart D.

A. A solution of 17-phenyl-18,19,20-trinor-PGF₂α, 776 mg.) and1-butaneboronic acid (225 mg.) in 25 ml. of methylene chloride is heatedat reflux. After 15 min. the methylene chloride is allowed to distilloff slowly. Fresh methylene chloride is added when the total volume isreduced to about one-half of the original volume. After 90 minutes, allof the methylene chloride is removed in vacuo to afford cyclic boronateof the starting prostaglandin.

B. The cyclic boronate is dissolved in 5 ml. of anhydrous, oxygen-freexylene and is treated with 2,2'-dipyridyl disulfide (660 mg.) andtriphenylphosphine (786 mg.). After 4 hours at 25° the reaction mixtureis diluted with 500 ml. of anhydrous, oxygen-free xylene and is heatedat reflux for 18 hr. The xylene is removed in vacuo to give a residue.The residue is taken up in 50 ml. of tetrahydrofuran containing 1 ml. of30 percent aqueous hydrogen peroxide (11.6 mmoles) and treated at 25° C.with a solution of sodium bicarbonate (1.68 g.) in 10 ml. of water. Thismixture is stirred vigorously for 30 min., then concentrated underreduced pressure to give a residue. The residue is taken up inbrine/ethyl acetate and extracted thoroughly with ethyl acetate. Thecombined extracts are washed with aqueous sodium bisulfate, water,aqueous sodium bicarbonate and brine, then dried over sodium sulfate andconcentrated to afford a residue of crude17-phenyl-18,19,20-trinor-PGF₂α, 1,15-lactone.

The crude lactone is purified by chromatography on 400 g. of neutralsilica packed and eluted (22 ml. fractions) with ethyl acetate. Thefractions which contained the product, based on TLC, are yieldingpurified 17-phenyl-18,19,20-trinor-PGF₂α, 1,15-lactone. The lactonecrystallized upon trituration and after two recrystallizations fromethyl acetate/hexane exhibits m.p. 116°-117° C.

The infrared spectrum exhibits peaks at 3460, 3400 sh, 3020, 1705, 1650,1605, 1495, 1325, 1300, 1265, 1150, 1100, 1040, 1020, 1000, 970, and 700cm.⁻¹ and the mass spectrum shows fragments at m/e 370 (M-18), 352, 334,308, 298, 261, 243, 225. (No M+ peak is apparent).

EXAMPLE 52 17-Phenyl-18,19,20-trinor-PGE₂, 1,15-lactone

(Formula LXXXII: Z₁, R₈, Y₁, R₅, and L₁ are as defined in Example 1, andR₇ is ##STR105##

Refer to Chart E.

A solution of 17-phenyl-18,19,20-trinor-PGE₂ (735 mg.),2,2'-dipyridyldisulfide (628 mg.) and triphenylphosphine (748 mg.) in 10ml. of anhydrous, oxygen-free xylene is stirred at 25° C. in anatmosphere of nitrogen for 2 hr. The mixture is then diluted with 400ml. of anhydrous, oxygen-free xylene, heated at reflux for 2.5 hrs., andevaporated under vacuum at 30° C. to give a residue. The residue ischromatographed on 100 g. of neutral silica, packed and eluted (8 ml.fractions) with 80 percent ether/hexane. The fractions containinghomogeneous product by TLC are combined to afford purified17-phenyl-18,19,20-trinor-PGE₂, 1,15-lactone. Two recrystallizationsfrom ether/hexane afford pure product, m.p. 81°-83° C. The infraredspectrum exhibits peaks at 3440, 3000, 1725, 1605, 1500, 1330, 1240,1160, 1145, 1085, 1045, 975, 745, 725 and 700 cm.⁻¹ and the massspectrum shows fragments at m/e 368 (M-18), 350, 332, 297, 296, 277,264, 259, 241 (no M+ apparent).

EXAMPLE 53 16-Phenoxy-17,18,19,20-tetranor-PGF₂α, 1,5-lactone

(Formula XXII: Z₁, R₈, Y₁, R₅, and L₁ are as defined in Example 1 and R₇is ##STR106##

Refer to Chart A.

Following the procedure of Example 1, part A, but substituting16-phenoxy-17,18,19,20-tetranor-PGF₂α for PGF₂α there is produced acrude product of 16-phenoxy-17,18,19,20-tetranor-PGF₂α, 1,15-lactone asa viscous yellow oil.

The crude product is purified by chromatography over neutral silicapacked in 50 percent ethyl acetate/hexane and eluted with 50 percentethyl acetate/hexane followed by 70 percent ethyl acetate hexane. Thosefractions containing homogeneous product as determined by TLC arecombined to afford crystalline 16-phenoxy-17,18,19,20-tetranor-PGF₂α,1,15-lactone. The lactone thus obtained is recrystallized from ethylacetate/hexane to afford pure product, m.p. 185°-186° C. The massspectrum of the trimethylsilyl derivative exhibits a peak at M+ 516.2738(theory for C₂₈ H₄₄ Si₂ O₅ : 516.2727) and fragments at m/e 501, 426,423, 409, 400, 333, 307, 217 and 181.

EXAMPLE 54 PGF₁α, 1,15-lactone or 15-epi-PGF₁α, 1,15-lactone

(Formula XXII: Z₁ is --(CH₂)₅ --, R₅, Y₁, M₁, L₁, and R₇ are as definedin Example 1).

Refer to Chart A.

Following the procedure of Example 1, part A, but substituting PGF₁α forPGF₂α there is obtained a crude product containing PGF₁α, 1,15-lactoneas a viscous yellow oil.

The crude product is purified by chromatography on 700 g. of neutralsilica, packed and eluted with 50 percent ethyl acetate/hexane. Thefirst 2 liters of eluate are discarded, after which 100 ml. fractionsare collected.

A minor product eluted first from the column (fractions 14-19) which ishomogeneous by TLC was combined to give 15-epi-PGF₁α, 1,15-lactone[(15R)-PGF₂α, 1,15-lactone]. The infrared spectrum exhibits peaks at3450, 1730, 1585, 1250, 1100, 970 and 735 cm.⁻¹ and the NMR spectrumshows peaks (δ_(TMS) ^(CDCl).sbsp.3) at 5.85-5.05 (vinyl and C-15;multiplet; 3H;, 4.25-3.85 (CHOH; multiplet; 2H) and 3.30 ppm (singlet,shifts downfield when sample is cooled; OH; 2H).

The major product, eluted later from the column (fractions 21-28), wascombined to afford purified PGF₁α, 1,15-lactone. The purified PGF₁α,1,15-lactone cyrstallizes upon trituration with ether, andrecrystallization (ethyl acetate/hexane) affords a pure sample, m.p.105°-106° C. The infrared spectrum exhibits peaks at umax 3520, 3480,3380, 1710, 1300, 1290, 1265, 1250, 1235, 1160, 1110, 1075, 1055, 1000,and 965 cm.⁻¹. The NMR spectrum shows peaks at 6.0-5.75 (vinyl;multiplet; 2H;, 5.60-5.00 (C-15H; multiplet; 1H), 4.25-3.80 (CHOH;multiplet; 2H) and 3.08 ppm (OH; singlet, shifts downfield on cooling;2H), and the mass spectrum shows fragments at 338 (M+), 320, 302, 266,249, 231.

EXAMPLE 55 PGE₁, 1,15-lactone

(Formula L: Z₁ is --(CH₂)₅ --, R₈, Y₁, R₅, L₁, and R₇ are as defined inExample 1).

Refer to Chart C.

Following the procedure of Example 22, but substituting PGF₁α,1,15-lactone for PGF₂α, 1,15-lactone, there is produced a crude productcontaining PGE₁, 1,15-lactone. Chromatography of the crude PGE₁,1,15-lactone over neutral silica packed in 20 percent ethylacetate/hexane affords pure PGE₁, 1,15-lactone, m.p. 87°-88° C.

The infrared spectrum exhibits peaks at 3390, 3320 sh, 1745, 1720, 1335,1255, 1235, 1195, 1180, 1160, 1100, 1075, and 980 cm.⁻¹ ; the NMRspectrum exhibits peaks (δ_(TMS) ^(CDCl).sbsp.3) at 6.1-5.85 (vinyl;multiplet; 2H), 5.45-5.05 (C-15H; multiplet; 1H), and 4.40-3.85 ppm(C-11H; multiplet; 1H); and the mass spectrum of the trimethylsilylether showed M+ 408.2694 : (theory for C₂₃ H₄₀ SiO₄ = 408.2606) as wellas peaks at m/e 393, 390, 380, 375, 365, 364, 318, 264, 150, and 99.

EXAMPLE 64 15-Methyl-PGF₂α, 1,15-lactone

(Formula XLIV: Z₁, Y₁, L₁, and R₇ are as defined in Example 1, and R₅ ismethyl).

Refer to Chart B.

15-Methyl-PGF₂α (1.97 g.) is transformed by the procedure of Example 20,part A, to a corresponding cycloboronate.

B. The reaction product of part A is then reacted with 40 ml. of xylene,2.10 g. of tripehnylphosphine, and 1.67 g. of 2,2'-dipyridyl disulfide,with stirring for 4 hr. at room temperature, thereby preparing thepyridine thiol ester of the reaction product of part A.

C. The reaction product of part B (about 40 ml.) is then divided intotwo equal volume aliquots which are separately lactonized as follows:

About one-half of the reaction product of part B (20 ml.) is thencombined with 1 l. of oxygen-free xylene and heated at reflux for 7 hr.The resulting mixture is then cooled to room temperature and the xyleneevaporated under reduced pressure.

D. The reaction product of part C is then treated with 100 ml. oftetrahydrofuran, 2 ml. of hydrogen peroxide, and 20 ml. of saturatedsodium bicarbonate. This mixture is then vigorously stirred at roomtemperature for 30 min., diluted with 50 ml. of water, and dried underreduced pressure. The residue is then diluted with brine, extracted withethyl acetate, and the organic layer washed with brine, dried overmagnesium sulfate, and evaporated under reduced pressure, yielding a 3.2g. residue. This residue is then chromatographed on 150 g. of silicagel, packed with 50 percent ethyl acetate in hexane, eluting with 50 to100 percent ethyl acetate in hexane and thereafter with 20 percentmethanol in ethyl acetate. Fractions containing pure title product arecombined, yielding 8.5 mg. The mass spectrum of the bis TMS derivativeshows parent peak at 494.3234 and other peaks at 479, 450, 423, 404,378, 367, 314, 351, and 217.

Following the procedure of the above examples there are obtained each ofthe various PG-type lactones described in the following Tables from eachof the respective corresponding free acids.

In interpreting these Tables, each formula listed in the Tablerepresents a prostaglandin-type lactone whose complete name is given bycombining the name provided in the respective legends below the formulawith the prefix found in the "Name" column in the tabular section of theTables for each example.

                                      Table A                                     __________________________________________________________________________     ##STR107##                                                                   PGF.sub.2α -type, 1,9-lactones                                           ##STR108##                                                                   13,14-dihydro-PGF.sub.2α -type, 1,9-lactones                             ##STR109##                                                                   PGF.sub.1α -type, 1,9-lactones                                           ##STR110##                                                                   13,14-dihydro-PGF.sub.1α -type, 1,9-lactones                             ##STR111##                                                                   13,14-didehydro-PGF.sub.2α -type, 1,9-lactones                           ##STR112##                                                                   13,14-didehydro-PGF.sub.1α -type, 1,9-lactones                           ##STR113##                                                                   2,2-difluoro-PGF.sub.2α -type, 1,9-lactones                              ##STR114##                                                                   2,2-difluoro-13,14-dihydro-PGF.sub.2α -type,                            1,9-lactones                                                                   ##STR115##                                                                   2,2-difluoro-PGF.sub.1α -type, 1,9-lactones                              ##STR116##                                                                   2,2-difluoro-13,14-dihydro-PGF.sub.1α -type,                            1,9-lactones                                                                   ##STR117##                                                                   13,14-didehydro-2,2-difluoro-PGF.sub.2α -type,                          1,9-lactones                                                                   ##STR118##                                                                   13,14-didehydro-2,2-difluoro-PGF.sub.1α -type,                          1,9-lactones                                                                   ##STR119##                                                                   cis-4,5-didehydro-PGF.sub.1α -type, 1,9-lactones                         ##STR120##                                                                   cis-4,5-didehydro-13,14-dihydro-PGF.sub.1α -type,                       1,9-lactones                                                                   ##STR121##                                                                   5-oxa-PGF.sub.1α -type, 1,9-lactones                                     ##STR122##                                                                   5-oxa-13,14-dihydro-PGF.sub.1α -type, 1,9-lactones                       ##STR123##                                                                   13,14-didehydro-cis-4,5-didehydro-PGF.sub.1α -type,                     1,9-lactones                                                                   ##STR124##                                                                   13,14-didehydro-5-oxa-PGF.sub.1α -type, 1,9-lactones                     ##STR125##                                                                   4-oxa-PGF.sub.1α -type, 1,9-lactones                                     ##STR126##                                                                   4-oxa-13,14-dihydro-PGF.sub.1α -type, 1,9-lactones                       ##STR127##                                                                   3-oxa-PGF.sub.1α -type, 1,9-lactones                                     ##STR128##                                                                   3-oxa-13,14-dihydro-PGF.sub.1α -type, 1,9-lactones                       ##STR129##                                                                   13,14-didehydro-4-oxa-PGF.sub.1α -type, 1,9-lactones                     ##STR130##                                                                   13,14-didehydro-3-oxa-PGF.sub.1α -type, 1,9-lactones                     ##STR131##                                                                   3,7-inter-m-phenylene-4,5,6-trinor-PGF.sub.1α -type,                    1,9-lactones                                                                   ##STR132##                                                                   3,7-inter-m-phenylene-4,5,6-trinor-13,14-                                     dihydro-PGF.sub.1α -type, 1,9-lactones                                   ##STR133##                                                                   3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-PGF.sub.1α -                   type, 1,9-lactones                                                             ##STR134##                                                                   3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-13,14-                               dihydro-PGF.sub.1α -type, 1,9-lactones                                   ##STR135##                                                                   13,14-didehydro-3,7-inter-m-phenylene-4,5,6-                                  trinor-PGF.sub.1α -type, 1,9-lactones                                    ##STR136##                                                                   13,14-didehydro-3,7-inter-m-phenylene-3-oxa-                                  4,5,6-trinor-PGF.sub.1α -type, 1,9-lactones                                      L.sub.1   M.sub.1                                                    Example                                                                            g m R.sub.3                                                                            R.sub.4                                                                            R.sub.5                                                                            ˜OH                                                                        Name                                               __________________________________________________________________________    A-1  1 3 methyl                                                                             hydrogen                                                                           hydrogen                                                                           α                                                                          16-methyl                                          A-2  1 3 methyl                                                                             hydrogen                                                                           methyl                                                                             α                                                                          15,16-dimethyl                                     A-3  1 3 methyl                                                                             hydrogen                                                                           hydrogen                                                                           β                                                                           15-epi-16-methyl                                   A-4  1 3 methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          16,16-dimethyl                                     A-5  1 3 methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15,16,16-trimethyl                                 A-6  1 3 methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           15-epi-16,16-dimethyl                              A-7  1 3 fluoro                                                                             hydrogen                                                                           hydrogen                                                                           α                                                                          16-fluoro                                          A-8  1 3 fluoro                                                                             hydrogen                                                                           methyl                                                                             α                                                                          15-methyl-16-fluoro                                A-9  1 3 fluoro                                                                             hydrogen                                                                           hydrogen                                                                           β                                                                           15-epi-16-fluoro                                   A-10 1 3 fluoro                                                                             fluoro                                                                             hydrogen                                                                           α                                                                          16,16-dufluoro                                     A-11 1 3 fluoro                                                                             fluoro                                                                             methyl                                                                             α                                                                          15-methyl-16,16-difluoro                           A-12 1 3 fluoro                                                                             fluoro                                                                             hydrogen                                                                           β                                                                           15-epi-16,16-difluoro                              A-13 1 3 hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          (title compound)                                   A-14 1 3 hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           15-epi                                             A-15 3 3 hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          2a,2b-dihomo                                       A-16 3 3 methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          2a,2b-dihomo-16,16-dimethyl                        A-17 3 3 methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          2a,2b-dihomo-15,16,16-trimethyl                    A-18 3 3 fluoro                                                                             fluoro                                                                             hydrogen                                                                           α                                                                          2a,2b-dihomo-16,16-difluoro                        A-19 3 3 fluoro                                                                             fluoro                                                                             methyl                                                                             α                                                                          2a,2b-dihomo-15-methyl-16,16-difluoro              __________________________________________________________________________

                                      Table B                                     __________________________________________________________________________     ##STR137##                                                                   PGF.sub.2.sbsb.α -type, 1,9-lactones                                     ##STR138##                                                                   13,14-dihydro-PGF.sub.2.sbsb.α -type, 1,9-lactones                       ##STR139##                                                                   PGF.sub.1.sbsb.α -type, 1,9-lactones                                     ##STR140##                                                                   13,14-dihydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                       ##STR141##                                                                   13,14-didehydro-PGF.sub.2.sbsb.α -type, 1,9-lactones                     ##STR142##                                                                   13,14-didehydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                     ##STR143##                                                                   2,2-difluoro-PGF.sub.2.sbsb.α -type, 1,9-lactones                        ##STR144##                                                                   2,2-difluoro-13,14-dihydro-PGF.sub.2.sbsb.α -type, 1,9-lactones          ##STR145##                                                                   2,2-difluoro-PGF.sub.1α -type, 1,15-lactones                             ##STR146##                                                                   2,2-difluoro-13,14-dihydro-PGF.sub.1.sbsb.α -type, 1,9-lactones          ##STR147##                                                                   13,14-didehydro-2,2-difluoro-PGF.sub.2.sbsb.α -type, 1,9-lactones        ##STR148##                                                                   13,14-didehydro-2,2-difluoro-PGF.sub.1.sbsb.α -type, 1,9-lactones        ##STR149##                                                                   cis-4,5-didehydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                   ##STR150##                                                                   cis-4,5-didehydro-13,14-dihydro-PGF.sub.1.sbsb.α -type,                 1,9-lactones                                                                   ##STR151##                                                                   5-oxa-PGF.sub.1.sbsb.α -type, 1,9-lactones                               ##STR152##                                                                   5-oxa-13,14-dihydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                 ##STR153##                                                                   13,14-didehydro-cis-4,5-didehydro-PGF.sub.1.sbsb.α -type,               1,9-lactones                                                                   ##STR154##                                                                   13,14-didehydro-5-oxa-PGF.sub.1.sbsb.α -type, 1,9-lactones               ##STR155##                                                                   4-oxa-PGF.sub.1.sbsb.α -type, 1,9-lactones                               ##STR156##                                                                   4-oxa-13,14-dihydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                 ##STR157##                                                                   3-oxa-PGF.sub.1.sbsb.α -type, 1,9-lactones                               ##STR158##                                                                   3-oxa-13,14-dihydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                 ##STR159##                                                                   13,14-didehydro-4-oxa-PGF.sub.1.sbsb.α -type, 1,9-lactones               ##STR160##                                                                   13,14-didehydro-3-oxa-PGF.sub.1.sbsb.α -type, 1,9-lactones               ##STR161##                                                                   3,7-inter-m-phenylene-4,5,6-trinor-PGF.sub.1.sbsb.α -type,              1,9-lactones                                                                   ##STR162##                                                                   3,7-inter-m-phenylene-4,5,6-trinor-13,14-                                     dihydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                             ##STR163##                                                                   3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-                                     PGF.sub.1.sbsb.α -type, 1,9-lactones                                     ##STR164##                                                                   3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-                                     13,14-dihydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                       ##STR165##                                                                   13,14-didehydro-3,7-inter-m-phenylene-4,5,6-                                  trinor-PGF.sub.1.sbsb.α -type, 1,9-lactones                              ##STR166##                                                                   13,14-didehydro-3,7-inter-m-phenylene-3-oxa-                                  4,5,6-trinor-PGF.sub.1.sbsb.α -type, 1,9-lactones                       __________________________________________________________________________                    L.sub.1                                                                            M.sub.1                                                  Example                                                                            g s T      R.sub.3                                                                            R.sub.4                                                                            R.sub.5                                                                            ˜OH                                                                        Name                                        __________________________________________________________________________    B-1  1 0        hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          16-phenoxy-17,18,19,20-tetranor             B-2  1 1 p-fluoro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          16-(p-fluorophenoxy)-17,18,19,20-                                             tetranor                                    B-3  1 1 m-chloro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          16-(m-chlorophenoxy)-17,18,19,20-                                             tetranor                                    B-4  1 1 m-trifluoro-                                                                         hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          16-(m-trifluoromethylphenoxy)-                       methyl                   17,18,19,20-tetranor                        B-5  1 0        hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-methyl-16-phenoxy-17,18,19,20-                                             tetranor                                    B-6  1 1 p-fluoro                                                                             hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-methyl-16-(p-fluorophenoxy)-                                               17,18,19,20-tetranor                        B-7  1 1 m-chloro                                                                             hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-methyl-16-(m-chlorophenoxy)-                                               17,18,19,20-tetranor                        B-8  1 1 m-trifluoro-                                                                         hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-methyl-16-(m-trifluoromethyl-                     methyl                   phenoxy)-17,18,19,20-tetranor               B-9  1 0        hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           15-epi-16-phenoxy-17,18,19,20-                                                tetranor                                    B-10 1 1 p-fluoro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           15-epi-16-(p-fluorophenoxy)-                                                  17,18,19,20-tetranor                        B-11 1 1 m-chloro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           15-epi-16-(m-chlorophenoxy)-                                                  17,18,19,20-tetranor                        B-12 1 1 m-trifluoro-                                                                         hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           15-epi-16-(m-trifluoromethylphen-                    methyl                   oxy)-17,18,19,20-tetranor                   B-13 1 0        methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          16-methyl-16-phenoxy-18,19,20-trinor        B-14 1 1 p-fluoro                                                                             methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          16-methyl-16-(p-fluorophenoxy)-                                               18,19,20-trinor                             B-15 1 1 m-chloro                                                                             methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          16-methyl-16-(m-chlorophenoxy)-                                               18,19,20-trinor                             B-16 1 1 m-trifluoro-                                                                         methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          16-methyl-16-(m-trifluoromethyl-                     methyl                   phenoxy)-18,19,20-trinor                    B-17 1 0        methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15,16-dimethyl-16-phenoxy-                                                    18,19,20-trinor                             B-18 1 1 p-fluoro                                                                             methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15,16-dimethyl-16-(p-fluorophen-                                              oxy)-18,19,20-trinor                        B-19 1 1 m-chloro                                                                             methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15,16-dimethyl-16-(m-chlorophenoxy)-                                          18,19,20-trinor                             B-20 1 1 m-trifluoro-                                                                         methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15,16-dimethyl-16-(m-trifluoro-                      methyl                   methylphenoxy)-18,19,20-trinor              B-21 1 0        methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           16-methyl-16-phenoxy-                                                         18,19,20-trinor                             B-22 1 1 p-fluoro                                                                             methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          15-epi-16-methyl-16-(p-fluorophen-                                            oxy)-18,19,20-trinor                        B-23 1 1 m-chloro                                                                             methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           15-epi-16-methyl-16-(m-chlorophen-                                            oxy)-18,19,20-trinor                        B-24 1 1 m-trifluoro-                                                                         methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           15-epi-16-methyl-16-(m-trifluoro-                    methyl                   methylphenoxy)-18,19,20-trinor              B-25 3 0        hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          2a,2b-dihomo-16-phenoxy-17,18,19,20-                                          tetranor                                    B-26 3 1 p-fluoro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          2a,2b-dihomo-16-(p-fluorophenoxy)-                                            17,18,19,20-tetranor                        B-27 3 1 m-chloro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          2a,2b-dihomo-16-(m-chlorophenoxy)-                                            17,18,19,20-tetranor                        B-28 3 1 m-trifluoro-                                                                         hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          2a,2b-dihomo-16-(m-trifluoromethyl-                  methyl                   phenoxy)-17,18,19,20-tetranor               B-29 3 0        hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          2a,2b-dihomo-15-methyl-16-phenoxy-                                            17,18,19,20-tetranor                        B-30 3 1 p-fluoro                                                                             hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          2a,2b-dihomo-15-methyl-16-(p-fluoro-                                          phenoxy)-17,18,19,20-tetranor               B-31 3 1 m-chloro                                                                             hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          2a,2b-dihomo-15-methyl-16-(m-chloro-                                          phenoxy)-17,18,19,20-tetranor-B-32 3 1 m                                      -trifluoro- hydrogen hydrogen methyl .al                                      pha. 2a,2b-dihomo-15-methyl-16-(m-tri-               methyl                   fluoromethylphenoxy)-17,18,19,20-                                             tetranor                                    __________________________________________________________________________

                                      Table C                                     __________________________________________________________________________     ##STR167##                                                                   18,19,20-trinor-PGF.sub.2.sbsb.α -type, 1,9-lactones                     ##STR168##                                                                   18,19,20-trinor-13,14-dihydro-PGF.sub.2.sbsb.α -type,                   1,9-lactones                                                                   ##STR169##                                                                   18,19,20-trinor-PGF.sub.1.sbsb.α -type,                                 1,9-lactones                                                                   ##STR170##                                                                   18,19,20-trinor-13,14-dihydro-PGF.sub.1.sbsb.α -type,                   1,9-lactones                                                                   ##STR171##                                                                   13,14-didehydro-18,19,20-trinor-PGF.sub.2.sbsb.α -type,                 1,9-lactones                                                                   ##STR172##                                                                   13,14-didehydro-18,19,20-trinor-PGF.sub.1.sbsb.α -type,                 1,9-lactones                                                                   ##STR173##                                                                   18,19,20-trinor-2,2-difluoro-PGF.sub.2.sbsb.α -type,                    1,9-lactones                                                                   ##STR174##                                                                   18,19,20-trinor-2,2-difluoro-13,14-dihydro-                                   PGF.sub.2.sbsb.α -type, 1,9-lactones                                     ##STR175##                                                                   18,19,20-trinor-2,2-difluoro-PGF.sub.1.sbsb.α -type,                    1,9-lactones                                                                   ##STR176##                                                                   18,19,20-trinor-2,2-difluoro-13,14-dihydro-                                   PGF.sub.1.sbsb.α -type, 1,9-lactones                                     ##STR177##                                                                   13,14-didehydro-18,19,20-trinor-2,2-difluoro-                                 PGF.sub.2.sbsb.α -type, 1,9-lactones                                     ##STR178##                                                                   13,14-didehydro-18,19,20-trinor-2,2-difluoro-                                 PGF.sub.1.sbsb.α -type, 1,9-lactones                                     ##STR179##                                                                   18,19,20-trinor-cis-4,5-didehydro-PGF.sub.1.sbsb.α -type,               1,9-lactones                                                                   ##STR180##                                                                   18,19,20-trinor-cis-4,5-didehydro-13,14-                                      dihydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                             ##STR181##                                                                   18,19,20-trinor-5-oxa-PGF.sub.1.sbsb.α -type, 1,9-                      lactones                                                                       ##STR182##                                                                   18,19,20-trinor-5-oxa-13,14-dihydro-PGF.sub.1.sbsb.α -                  type, 1,9-lactones                                                             ##STR183##                                                                   13,14-didehydro-18,19,20-trinor-cis-4,5-                                      didehydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                           ##STR184##                                                                   13,14-didehydro-18,19,20-trinor-5-oxa-PGF.sub.1.sbsb.α -                type, 1,9-lactones                                                             ##STR185##                                                                   18,19,20-trinor-4-oxa-PGF.sub.1.sbsb.α -type, 1,9-lactones               ##STR186##                                                                   18,19,20-trinor-4-oxa-13,14-dihydro-PGF.sub.1.sbsb.α -                  type, 1,9-lactones                                                             ##STR187##                                                                   18,19,20-trinor-3-oxa-PGF.sub.1.sbsb.α -type, 1,9-lactones               ##STR188##                                                                   18,19,20-trinor-3-oxa-13,14-dihydro-PGF.sub.1.sbsb.α -                  type, 1,9-lactones                                                             ##STR189##                                                                   13,14-didehydro-18,19,20-trinor-4-oxa-PGF.sub.1.sbsb.α -                type, 1,9-lactones                                                             ##STR190##                                                                   13,14-didehydro-18,19,20-trinor-3-oxa-PGF.sub.1.sbsb.α -                type, 1,9-lactones                                                             ##STR191##                                                                   3,7-inter-m-phenylene-4,5,6,18,19,20-hexanor-                                 PGF.sub.1.sbsb.α -type, 1,9-lactones                                     ##STR192##                                                                   3,7-inter-m-phenylene-4,5,6,18,19,20-hexanor-                                 13,14-dihydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                       ##STR193##                                                                   3,7-inter-m-phenylene-3-oxa-4,5,6,18,19,20-                                   hexanor-PGF.sub.1.sbsb.α -type, 1,9-lactones                             ##STR194##                                                                   3,7-inter-m-phenylene-3-oxa-4,5,6,18,19,20-hex-                               anor-13,14-dihydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                  ##STR195##                                                                   13,14-didehydro-3,7-inter-m-phenylene-                                        4,5,6,18,19,20-hexanor-PGF.sub.1.sbsb.α -type, 1,9-lactones              ##STR196##                                                                   13,14-didehydro-3,7-inter-m-phenylene-3-oxa-                                  4,5,6,18,19,20-hexanor-PGF.sub.1.sbsb.α -type, 1,9-lactones             __________________________________________________________________________                    L.sub.1                                                                            M.sub.1                                                  Example                                                                            g s  T      R.sub.3                                                                            R.sub.4                                                                            R.sub.5                                                                           ˜OH                                                                           Name                                     __________________________________________________________________________    C-1  1 0        hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          17-phenyl                                   C-2  1 1 p-fluoro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          17-(p-fluorophenyl)                         C-3  1 1 m-chloro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          17-(m-chlorophenyl)                         C-4  1 1 m-trifluoro-                                                                         hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          17-(m-trifluoromethylphenyl)                         methyl                                                               C-5  1 0        hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-methyl-17-phenyl                         C-6  1 1 p-fluoro                                                                             hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-methyl-17-(p-fluorophenyl)               C-7  1 1 m-chloro                                                                             hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-methyl-17-(m-chlorophenyl)               C-8  1 1 m-trifluoro-                                                                         hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-methyl-17-(m-trifluoromethyl-                     methyl                   phenyl)                                     C-9  1 0        hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           15-epi-17-phenyl                            C-10 1 1 p-fluoro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           15-epi-17-(p-fluorophenyl)                  C-11 1 1 m-chloro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           15-epi-17-(m-chlorophenyl)                  C-12 1 1 m-trifluoro-                                                                         hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           15-epi-17-(m-trifluoromethyl-                        methyl                   phenyl)                                     C-13 1 0        methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          16,16-dimethyl-17-phenyl                    C-14 1 1 p-fluoro                                                                             methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          16,16-dimethyl-17-(p-fluorophenyl)          C-15 1 1 m-chloro                                                                             methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          16,16-dimethyl-17-(m-chlorophenyl)          C-16 1 1 m-trifluoro-                                                                         methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          16,16-dimethyl-17-(m-trifluoro-                      methyl                   methylphenyl)                               C-17 1 0        methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15,16,16-trimethyl-17-phenyl                C-18 1 1 p-fluoro                                                                             methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15,16,16-trimethyl-17-(p-fluoro-                                              phenyl)                                     C-19 1 1 m-chloro                                                                             methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15,16,16-trimethyl-17-(m-chloro-                                              phenyl)                                     C-20 1 1 m-trifluoro-                                                                         methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15,16,16-trimethyl-17-(m-trifluoro-                  methyl                   methylphenyl)                               C-21 1 0        methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           15-epi-16,16-dimethyl-17-phenyl             C-22 1 1 p-fluoro                                                                             methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           15-epi-16,16-dimethyl-17-(p-fluoro-                                           phenyl)                                     C-23 1 1 m-chloro                                                                             methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           15-epi-16,16-dimethyl-17-(m-chloro-                                           phenyl)                                     C-24 1 1 m-trifluoro-                                                                         methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           15-epi-16,16-dimethyl-17-(m-tri-                     methyl                   fluoromethylphenyl)                         C-25 3 0        hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          2a,2b-dihomo-17-phenyl                      C-26 3 1 p-fluoro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          2a,2b-dihomo-17-(p-fluorophenyl)            C-27 3 1 m-chloro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          2a,2b-dihomo-17-(m-chlorophenyl)            C-28 3 1 m-trifluoro-                                                                         hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          2a,2b-dihomo-17-(m-trifluoromethyl-                  methyl                   phenyl)                                     C-29 3 0        hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          2a,2b-dihomo-15-methyl-17-phenyl            C-30 3 1 p-fluoro                                                                             hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          2a,2b-dihomo-15-methyl-17-(p-                                                 fluorophenyl)                               C-31 3 1 m-chloro                                                                             hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          2a,2b-dihomo-15-methyl-17-(m-                                                 chlorophenyl)                               C-32 3 1 m-trifluoro-                                                                         hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          2a,2b-dihomo-15-methyl-17-(m-tri-                    methyl                   fluoromethylphenyl)                         C-33 1 0        fluoro                                                                             fluoro                                                                             hydrogen                                                                           α                                                                          16,16-difluoro-17-phenyl                    C-34 1 1 p-fluoro                                                                             fluoro                                                                             fluoro                                                                             hydrogen                                                                           α                                                                          16,16-difluoro-17-(p-fluorophenyl)          C-35 1 1 m-chloro                                                                             fluoro                                                                             fluoro                                                                             hydrogen                                                                           α                                                                          16,16-difluoro-17-(m-chlorophenyl)          C-36 1 1 m-trifluoro-                                                                         fluoro                                                                             fluoro                                                                             hydrogen                                                                           α                                                                          16,16-difluoro-17-(m-trifluoro-                      methyl                   methylphenyl)                               C-37 1 0        fluoro                                                                             fluoro                                                                             methyl                                                                             α                                                                          15-methyl-16,16-difluoro-17-phenyl          C-38 1 1 p-fluoro                                                                             fluoro                                                                             fluoro                                                                             methyl                                                                             α                                                                          15-methyl-16,16-difluoro-17-(p-                                               fluorophenyl)                               C-39 1 1 m-chloro                                                                             fluoro                                                                             fluoro                                                                             methyl                                                                             α                                                                          15-methyl-16,16-difluoro-17-(m-                                               chlorophenyl                                C-40 1 1 m-trifluoro-                                                                         fluoro                                                                             fluoro                                                                             methyl                                                                             α                                                                          15-methyl-16,16-difluoro-17-(m-                      methyl                   trifluoromethylphenyl)                      C-41 1 0        fluoro                                                                             fluoro                                                                             hydrogen                                                                           α                                                                          16,16-difluoro-17-phenyl                    C-42 1 1 p-fluoro                                                                             fluoro                                                                             fluoro                                                                             hydrogen                                                                           α                                                                          16,16-difluoro-17-(p-fluorophenyl)          C-43 1 1 m-chloro                                                                             fluoro                                                                             fluoro                                                                             hydrogen                                                                           β                                                                           15-epi-16,16-difluoro-17-(m-chloro-                                           phenyl                                      C-44 1 1 m-trifluoro-                                                                         fluoro                                                                             fluoro                                                                             hydrogen                                                                           β                                                                           15-epi-16,16-difluoro-17-(m-tri-                     methyl                   fluoromethylphenyl)                         __________________________________________________________________________

                                      Table D                                     __________________________________________________________________________     ##STR197##                                                                   PGF.sub.3.sbsb.α -type, 1,9-lactones                                     ##STR198##                                                                   13,14-dihydro-PGF.sub.3.sbsb.α -type, 1,9-lactones                       ##STR199##                                                                   5,6-dihydro-PGF.sub.3.sbsb.α -type, 1,9-lactones                         ##STR200##                                                                   5,6,13,14-tetrahydro-PGF.sub.3.sbsb.α -type, 1,9-lactones                ##STR201##                                                                   13,14-didehydro-PGF.sub.3.sbsb.α -type, 1,9-lactones                     ##STR202##                                                                   13,14-didehydro-5,6-dihydro-PGF.sub.3.sbsb.α -type, 1,9-                lactones                                                                       ##STR203##                                                                   2,2-difluoro-PGF.sub.3.sbsb. α -type, 1,9-lactones                       ##STR204##                                                                   2,2-difluoro-13,14-dihydro-PGF.sub.3.sbsb.α -type,                      1,9-lactones                                                                   ##STR205##                                                                   2,2-difluoro-5,6-dihydro-PGF.sub.3.sbsb.α -type, 1,9-                   lactones                                                                       ##STR206##                                                                   2,2-difluoro-5,6,13,14-tetrahydro-PGF.sub.3.sbsb.α                      type, 1,9-lactones                                                             ##STR207##                                                                   13,14-didehydro-2,2-difluoro-PGF.sub.3.sbsb.α -types                    1,9-lactones                                                                   ##STR208##                                                                   13,14-didehydro-2,2-difluoro-5,6-dihydro-PGF.sub.3.sbsb.α -             type, 1,9-lactones                                                             ##STR209##                                                                   cis,cis-4,5,17,18-tetradehydro-PGF.sub.1.sbsb.α -type,                  1,9-lactones                                                                   ##STR210##                                                                   cis,cis-4,5,17,18-tetradehydro-13,14-dihydro-                                 PGF.sub.1.sbsb.α -type, 1,9-lactones                                     ##STR211##                                                                   5-oxa-cis-17,18-didehydro-PGF.sub.1.sbsb.α -type,                       1,9-lactones                                                                   ##STR212##                                                                   5-oxa-13,14-dihydro-cis-17,18-didehydro-PGF.sub.1.sbsb.α -              type, 1,9-lactones                                                             ##STR213##                                                                   13,14-didehydro-cis,cis-4,5,17,18-tetradehydro-                               PGF.sub.1.sbsb.α -type, 1,9-lactones                                     ##STR214##                                                                   13,14-didehydro-5-oxa-cis-17,18-didehydro-                                    PGF.sub.1.sbsb.α -type, 1,9-lactones                                     ##STR215##                                                                   4-oxa-cis-17,18-didehydro-PGF.sub.1.sbsb.α -type, 1,9-                  lactones                                                                       ##STR216##                                                                   4-oxa-13,14-dihydro-17,18-didehydro-PGF.sub.1.sbsb.α -                  type, 1,9-lactones                                                             ##STR217##                                                                   3-oxa-cis-17,18-didehydro-PGF.sub.1.sbsb.α -type, 1,9-lactones           ##STR218##                                                                   3-oxa-13,14-dihydro-cis-17,18-didehydro-PGF.sub.1.sbsb.α -              type, 1,9-lactones                                                             ##STR219##                                                                   13,14-didehydro-4-oxa-cis-17,18-didehydro-                                    PGF.sub.1.sbsb.α -type, 1,9-lactones                                     ##STR220##                                                                   13,14-didehydro-3-oxa-cis-17,18-didehydro-                                    PGF.sub.1.sbsb.α -type, 1,9-lactones                                     ##STR221##                                                                   3,7-inter-m-phenylene-4,5,6-trinor-cis-17,18-                                 didehydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                           ##STR222##                                                                   3,7-inter-m-phenylene-4,5,6-trinor-13,14-dihydro-                             cis-17,18-didehydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                 ##STR223##                                                                   3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-cis-                                 17,18-didehydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                     ##STR224##                                                                   3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-13,14-                               dihydro-cis-17,18-didehydro-PGF.sub.1.sbsb.α -type, 1,9-                lactones                                                                       ##STR225##                                                                   13,14-didehydro-3,7-inter-m-phenylene-4,5,6-                                  trinor-cis-17,18-didehydro-PGF.sub.1.sbsb.α -type, 1,9-                 lactones                                                                       ##STR226##                                                                   13,14-didehydro-3,7-inter-m-phenylene-3-oxa-                                  4,5,6-trinor-cis-17,18-didehydro-PGF.sub.1.sbsb.α -type,                1,9-lactones                                                                  __________________________________________________________________________           L.sub.1                                                                             M.sub.1                                                          Example                                                                            g R.sub.3                                                                             R.sub.4                                                                             R.sub.5                                                                            ˜OH                                                                         Name                                              __________________________________________________________________________    D-1  1 methyl                                                                              hydrogen                                                                            hydrogen                                                                           α                                                                           16-methyl                                         D-2  1 methyl                                                                              hydrogen                                                                            methyl                                                                             α                                                                           15,16-dimethyl                                    D-3  1 methyl                                                                              hydrogen                                                                            hydrogen                                                                           β                                                                            15-epi-16-methyl                                  D-4  1 methyl                                                                              methyl                                                                              hydrogen                                                                           α                                                                           16,16-dimethyl                                    D-5  1 methyl                                                                              methyl                                                                              methyl                                                                             α                                                                           15,16,16-trimethyl                                D-6  1 methyl                                                                              methyl                                                                              hydrogen                                                                           α                                                                           16,16-dimethyl                                    D-7  1 fluoro                                                                              hydrogen                                                                            hydrogen                                                                           β                                                                            15-epi-16-fluoro                                  D-8  1 fluoro                                                                              hydrogen                                                                            methyl                                                                             α                                                                           15-methyl-16-fluoro                               D-9  1 fluoro                                                                              hydrogen                                                                            hydrogen                                                                           β                                                                            15-epi-16-fluoro                                  D-10 1 fluoro                                                                              fluoro                                                                              hydrogen                                                                           α                                                                           16,16-difluoro                                    D-11 1 fluoro                                                                              fluoro                                                                              methyl                                                                             α                                                                           15-methyl-16,16-difluoro                          D-12 1 fluoro                                                                              fluoro                                                                              hydrogen                                                                           β                                                                            15-epi-16,16-difluoro                             D-13 1 hydrogen                                                                            hydrogen                                                                            hydrogen                                                                           α                                                                           (title compound)                                  D-14 1 hydrogen                                                                            hydrogen                                                                            methyl                                                                             α                                                                           15-methyl                                         D-15 3 hydrogen                                                                            hydrogen                                                                            hydrogen                                                                           α                                                                           2a,2b-dihomo                                      D-16 3 hydrogen                                                                            hydrogen                                                                            methyl                                                                             α                                                                           2a,2b-dihomo-15-methyl                            D-17 3 methyl                                                                              methyl                                                                              hydrogen                                                                           α                                                                           2a,2b-dihomo-16,16-dimethyl                       D-18 3 methyl                                                                              methyl                                                                              methyl                                                                             α                                                                           2a,2b-dihomo-15,16,16-trimethyl                   D-19 3 fluoro                                                                              fluoro                                                                              hydrogen                                                                           α                                                                           2a,2b-dihomo-16,16-difluoro                       D-20 3 fluoro                                                                              fluoro                                                                              methyl                                                                             α                                                                           2a,2b-dihomo-15-methyl-                                                       16,16-difluoro                                    __________________________________________________________________________

                                      Table E                                     __________________________________________________________________________     ##STR227##                                                                   cis-13-PGF.sub.2.sbsb.α -type, 1,9-lactones                              ##STR228##                                                                   cis-13-PGF.sub.1.sbsb.α -type, 1,9-lactones                              ##STR229##                                                                   2,2-difluoro-cis-13-PGF.sub.2.sbsb.α -type, 1,9-lactones                 ##STR230##                                                                   2,2-difluoro-cis-13-PGF.sub.1.sbsb.α -type, 1,9-lactones                 ##STR231##                                                                   cis-4,5-didehydro-cis-13-PGF.sub.1.sbsb.α -type, 1,9-lactones            ##STR232##                                                                   5-oxa-cis-13-PGF.sub.1.sbsb.α -type, 1,9-lactones                        ##STR233##                                                                   5-oxa-cis-13-PGF.sub.1.sbsb.α -type, 1,9-lactones                        ##STR234##                                                                   3-oxa-cis-13-PGF.sub.1.sbsb.α -type, 1,9-lactones                        ##STR235##                                                                   3,7-inter-m-phenylene-4,5,6-trinor-cis-13-                                    PGF.sub.1.sbsb.α -type, 1,9-lactones                                     ##STR236##                                                                   3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-                                     cis-13-PGD.sub.1 -type, 1,9-lactones                                                   L.sub.1                                                              Example                                                                            g m R.sub.3                                                                            R.sub.4                                                                            R.sub.5                                                                            ˜O                                                                            Name                                            __________________________________________________________________________    E-1  1 3 methyl                                                                             hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-16-methyl                                   E-2  1 3 methyl                                                                             hydrogen                                                                           methyl                                                                             α                                                                          15-epi-15,16-dimethyl                              E-3  1 3 methyl                                                                             hydrogen                                                                           hydrogen                                                                           β                                                                           16-methyl                                          E-4  1 3 methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          15-epi-16,16-dimethyl                              E-5  1 3 methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15-epi-15,16,16-trimethyl                          E-6  1 3 methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           16,16-dimethyl                                     E-7  1 3 fluoro                                                                             hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-16-fluoro                                   E-8  1 3 fluoro                                                                             hydrogen                                                                           methyl                                                                             α                                                                          15-epi-15-methyl-16-fluoro                         E-9  1 3 fluoro                                                                             hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-16-fluoro                                   E-10 1 3 fluoro                                                                             fluoro                                                                             hydrogen                                                                           α                                                                          15-epi-16,16-difluoro                              E-11 1 3 fluoro                                                                             fluoro                                                                             methyl                                                                             α                                                                          15-epi-15-methyl-16,16-difluoro                    E-12 1 3 fluoro                                                                             fluoro                                                                             methyl                                                                             β                                                                           15-methyl-16,16-difluoro                           E-13 1 3 hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi                                             E-14 3 3 hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-21,2b-dihomo                                E-15 3 3 methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          15-epi-2a,2b-dihomo-16,16-dimethyl                 E-16 3 3 methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15-epi-2a,2b-dihomo-15,16,16-trimethyl             E-17 3 3 fluoro                                                                             fluoro                                                                             hydrogen                                                                           α                                                                          15-epi-2a,2b-dihomo-16,16-difluoro                 E-18 3 3 fluoro                                                                             fluoro                                                                             methyl                                                                             α                                                                          15-epi-2a,2b-dihomo-15-methyl-16,16-di-                                       fluoro                                             __________________________________________________________________________

                                      Table F                                     __________________________________________________________________________     ##STR237##                                                                   cis-13-PGF.sub.2.sbsb.α -type, 1,9-lactones                              ##STR238##                                                                   cis-13-PGF.sub.1.sbsb.α -type, 1,9-lactones                              ##STR239##                                                                   2,2-difluoro-cis-13-PGF.sub.2.sbsb.α -type, 1,9-lactones                 ##STR240##                                                                   2,2-difluoro-cis-13-PGF.sub.1.sbsb.α -type, 1,9-lactones                 ##STR241##                                                                   cis-4,5-didehydro-cis-13-PGF.sub.1.sbsb.α -type, 1,9-lactones            ##STR242##                                                                   5-oxa-cis-13-PGF.sub.1.sbsb.α -type, 1,9-lactones                        ##STR243##                                                                   4-oxa-cis-13-PGF.sub.1.sbsb.α -type, 1,9-lactones                        ##STR244##                                                                   3-oxa-cis-13-PGF.sub.1.sbsb.α -type, 1,9-lactones                        ##STR245##                                                                   3,7-inter-m-phenylene-4,5,6-trinor-cis-13-                                    PGF.sub.1.sbsb.α -type, 1,9-lactones                                     ##STR246##                                                                   3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-                                     cis-13-PGF.sub.1.sbsb.α -type, 1,9-lactones                             L.sub.1                                                                       Example                                                                           g s T     R.sub.3                                                                            R.sub.4                                                                            R.sub.5                                                                            ˜O                                                                         Name                                          __________________________________________________________________________    F-1 1 0       hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-16-phenoxy-17,18,19,20-                                                tetranor                                      F-2 1 1 p-fluoro                                                                            hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-16-(p-fluorophenoxy)-                                                  17,18,19,20-tetranor                          F-3 1 1 m-chloro                                                                            hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-16-(m-chlorophenoxy)-                                                  17,18,19,20-tetranor                          F-4 1 1 m-trifluoro-                                                                        hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-16-(m-trifluoromethylphen-                     methyl                  oxy)-17,18,19,20-tetranor                     F-5 1 0       hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-15-methyl-16-phenoxy-                                                  17,18,19,20-tetranor                          F-6 1 1 p-fluoro                                                                            hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-15-methyl-16-(p-fluoro-                                                phenoxy)-17,18,19,20-tetranor                 F-7 1 1 m-chloro                                                                            hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-15-methyl-16-(m-chlorophen-                                            oxy)-17,18,19,20-tetranor                     F-8 1 1 m-trifluoro-                                                                        hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-15-methyl-16-(m-trifluoro-                     methyl                  methylphenoxy)-17,18,19,20-tetranor           F-9 1 0       hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           16-phenoxy-17,18,19,20-tetranor               F-10                                                                              1 1 p-fluoro                                                                            hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           16-(p-fluorophenoxy)-17,18,19,20-                                             tetranor                                      F-11                                                                              1 1 m-chloro                                                                            hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           16-(m-chlorophenoxy)-17,18,19,20-                                             tetranor                                      F-12                                                                              1 1 m-trifluoro-                                                                        hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           16-(m-trifluoromethylphenoxy)-                        methyl                  17,18,19,20-tetranor                          F-13                                                                              1 0       methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          15-epi-16-methyl-16-phenoxy-                                                  18,19,20-trinor                               F-14                                                                              1 1 p-fluoro                                                                            methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          15-epi-16-methyl-16-(p-fluoro-                                                phenoxy)-18,19,20-trinor                      F-15                                                                              1 1 m-chloro                                                                            methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          15-epi-16-methyl-16-(m-chlorophen-                                            oxy)-18,19,20-trinor                          F-16                                                                              1 1 m-trifluoro-                                                                        methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          15-epi-16-methyl-16-(m-trifluoro-                     methyl                  methylphenoxy)-18,19,20-trinor                F-17                                                                              1 0       methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15-epi-15,16-dimethyl-16-phenoxy-                                             18,19,20-trinor                               F-18                                                                              1 1 p-fluoro                                                                            methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15-epi-15,16-dimethyl-16-(p-fluoro-                                           phenoxy)-18,19,20-trinor                      F-19                                                                              1 1 m-chloro                                                                            methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15-epi-15,16-dimethyl-16-(m-chloro-                                           phenoxy)-18,19,20-trinor                      F-20                                                                              1 1 m-trifluoro-                                                                        methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15-epi-15,16-dimethyl-16-(m-tri-                      methyl                  fluoromethylphenoxy)-18,19,20-                                                trinor                                        F-21                                                                              1 0       methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           16-methyl-16-phenoxy-18,19,20-tri-                                            nor                                           F-22                                                                              1 1 p-fluoro                                                                            methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           16-methyl-16-(p-fluorophenoxy)-                                               18,19,20-trinor                               F-23                                                                              1 1 m-chloro                                                                            methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           16-methyl-16-(m-chlorophenoxy)-                                               18,19,20-trinor                               F-24                                                                              1 1 m-trifluoro-                                                                        methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           16-methyl-16-(m-trifluoromethyl-                      methyl                  phenoxy)-18,19,20-trinor                      F-25                                                                              3 0       hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-2a,2b-dihomo-16-phenoxy-                                               17,18,19,20-tetranor                          F-26                                                                              3 1 p-fluoro                                                                            hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-2a,2b,-dihomo-16-(p-fluoro-                                            phenoxy)-17,18,19,20-tetranor                 F-27                                                                              3 1 m-chloro                                                                            hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-2a,2b-dihomo-16-(m-chloro-                                             phenoxy)-17,18,19,20-tetranor                 F-28                                                                              3 1 m-trifluoro-                                                                        hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-2a,2b,-dihomo-16-(m-trifluoro-                 methyl                  methylphenoxy)-17,18,19,20-tetranor           F-29                                                                              3 0       hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-2a,2b-dihomo-15-methyl-16-                                             phenoxy-17,18,19,20-tetranor                  F-30                                                                              3 1 p-fluoro                                                                            hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-2a,2b-dihomo-15-methyl-16-                                             (p-fluorophenoxy)-18,19,20-tetranor           F-31                                                                              3 1 m-chloro                                                                            hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-2a,2b-dihomo-15-methyl-16-                                             (m-chlorophenoxy)-17,18,19,20-                                                tetranor                                      F-32                                                                              3 1 m-trifluoro-                                                                        hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-2a,2b-dihomo-15-methyl-16-                     methyl                  (m-trifluoromethylphenoxy)-                                                   17,18,19,20-tetranor                          __________________________________________________________________________

                                      TABLE G                                     __________________________________________________________________________     ##STR247##                                                                   18,19,20-trinor-cis-13-PGF.sub.2.sbsb.α -type, 1,9-lactones              ##STR248##                                                                   18,19,20-trinor-cis-13-PGF.sub.1.sbsb.α -type, 1,9-lactones              ##STR249##                                                                   18,19,20-trinor-2,2-difluoro-cis-13-PGF.sub.2.sbsb.α -                  type, 1,9-lactones                                                             ##STR250##                                                                   18,19,20-trinor-2,2-difluoro-cis-13-PGF.sub.1.sbsb.α -                  type, 1,9-lactones                                                             ##STR251##                                                                   18,19,20-trinor-cis-4,5-didehydro-cis-13-PGF.sub.1.sbsb.α -             type, 1,9-lactones                                                             ##STR252##                                                                   18,19,20-trinor-5-oxa-cis-13-PGF.sub.1.sbsb.α -type,                    1,9-lactones                                                                   ##STR253##                                                                   18,19,20-trinor-4-oxa-cis-PGF.sub.1.sbsb.α -type,                       1,9-lactones                                                                   ##STR254##                                                                   18,19,20-trinor-3-oxa-cis-13-PGF.sub.1.sbsb.α -type,                    1,9-lactones                                                                   ##STR255##                                                                   3,7-inter-m-phenylene-4,5,6,18,19,20-hexanor-                                 cis-13-PGF.sub.1.sbsb.α -type, 1,9-lactones                              ##STR256##                                                                   3,7-inter-m-phenylene-3-oxa-4,5,6,18,19,20-                                   hexanor-cis-13-PGF.sub.1.sbsb.α -type, 1,9-lactones                     __________________________________________________________________________                    L.sub.1                                                                            M.sub.1                                                  Example                                                                            g s  T      R.sub.3                                                                            R.sub.4                                                                            R.sub.5                                                                           ˜OH                                                                           Name                                     __________________________________________________________________________    G-1  1 0        hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-17-phenyl                            G-2  1 1 p-fluoro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-17-(p-fluorophenyl)                  G-3  1 1 m-chloro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-17-(m-chlorophenyl)                  G-4  1 1 m-trifluoro-                                                                         hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-17-(m-trifluoromethylphenyl)                  methyl                                                               G-5  1 0        hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-15-methyl-17-phenyl                  G-6  1 1 p-fluoro                                                                             hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-15-methyl-17-(p-fluorophenyl)        G-7  1 1 m-chloro                                                                             hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-15-methyl-17-(m-chlorophenyl)        G-8  1 1 m-trifluoro-                                                                         hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-15-methyl-17-(m-trifluoro-                    methyl                   methylphenyl)                               G-9  1 0        hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           17-phenyl                                   G-10 1 1 p-fluoro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           17-(p-fluorophenyl)                         G-11 1 1 m-chloro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           17-(m-chlorophenyl)                         G-12 1 1 m-trifluoro-                                                                         hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           β                                                                           17-(m-trifluoromethylphenyl)                         methyl                                                               G-13 1 0        methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          15-epi-16,16-dimethyl-17-phenyl             G-14 1 1 p-fluoro                                                                             methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          15-epi-16,16-dimethyl-17-(p-fluoro-                                           phenyl)                                     G-15 1 1 m-chloro                                                                             methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          15-epi-16,16-dimethyl-17-(m-chloro-                                           phenyl)                                     G-16 1 1 m-trifluoro-                                                                         methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          15-epi-16,16-dimethyl-17-(m-tri-                     methyl                   fluoromethylphenyl)                         G-17 1 0        methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15-epi-15,16-trimethyl-17-phenyl            G-18 1 1 p-fluoro                                                                             methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15-epi-15,16,16-trimethyl-17-(p-                                              fluorophenyl)                               G-19 1 1 m-chloro                                                                             methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15-epi-15,16,16-trimethyl-17-(m-                                              chlorophenyl)                               G-20 1 1 m-trifluoro-                                                                         methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15-epi-15,16,16-trimethyl-(m-tri-                    methyl                   fluoromethylphenyl)                         G-21 1 0        methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           16,16-dimethyl-17-phenyl                    G-22 1 1 p-fluoro                                                                             methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           16,16-dimethyl-17-(p-fluorophenyl)          G-23 1 1 m-chloro                                                                             methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           16,16-dimethyl-17-(m-chlorophenyl)          G-24 1 1 m-trifluoro-                                                                         methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           16,16-dimethyl-17-(m-trifluoro-                      methyl                   methylphenyl)                               G-25 3 0        hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-2a,2b,-dihomo-17-phenyl              G-26 3 1 p-fluoro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-2a,2b,-dihomo-17-(p-fluoro-                                            phenyl)                                     G-27 3 1 m-chloro                                                                             hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-2a,2b,-dihomo-17-(m-chloro-                                            phenyl)                                     G-28 3 1 m-trifluoro-                                                                         hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-2a,2b,-dihomo-17-(m-tri-                      methyl                   fluoromethylphenyl)                         G-29 3 0        hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-2a,2b-dihomo-15-methyl-17-                                             phenyl                                      G-30 3 1 p-fluoro                                                                             hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-2a,2b-dihomo-15-methyl-17-                                             (p-fluorophenyl)                            G-31 3 1 m-chloro                                                                             hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-2a,2b-dihomo-15-methyl-17-                                             (m-chlorophenyl)                            G-32 3 1 m-trifluoro-                                                                         hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-2a,2b-dihomo-15-methyl-17-                    methyl                   (m-trifluoromethylphenyl)                   G-33 1 0        fluoro                                                                             fluoro                                                                             hydrogen                                                                           α                                                                          15-epi-16,16-difluoro-17-phenyl             G-34 1 1 p-fluoro                                                                             fluoro                                                                             fluoro                                                                             hydrogen                                                                           α                                                                          15-epi-16,16-difluoro-17-(p-fluoro-                                           phenyl)                                     G-35 1 1 m-chloro                                                                             fluoro                                                                             fluoro                                                                             hydrogen                                                                           α                                                                          15-epi-16,16-difluoro-17-(m-chloro-                                           phenyl)                                     G-36 1 1 m-trifluoro-                                                                         flouro                                                                             fluoro                                                                             hydrogen                                                                           α                                                                          15-epi-16,16-diflouro-17-(m-tri-                     methyl                   fluoromethylphenyl)                         G-37 1 0        fluoro                                                                             fluoro                                                                             methyl                                                                             α                                                                          15-epi-15-methyl-16,16-difluoro-17-                                           phenyl                                      G-38 1 1 p-fluoro                                                                             fluoro                                                                             fluoro                                                                             methyl                                                                             α                                                                          15-epi-15-methyl-16,16-difluoro-17-                                           (p-fluorophenyl)                            G-39 1 1 m-chloro                                                                             fluoro                                                                             fluoro                                                                             methyl                                                                             α                                                                          15-epi-15-methyl-16,16-difluoro-17-                                           (m-chlorophenyl)                            G-40 1 1 m-trifluoro-                                                                         fluoro                                                                             fluoro                                                                             methyl                                                                             α                                                                          15-epi-15-methyl-16,16-difluoro-17-                  methyl                   (m-trifluoromethylphenyl)                   G-41 1 0        fluoro                                                                             fluoro                                                                             hydrogen                                                                           β                                                                           16,16-difluoro-17-phenyl                    G-42 1 1 p-fluoro                                                                             fluoro                                                                             fluoro                                                                             hydrogen                                                                           β                                                                           16,16-difluoro-17-(p-fluorophenyl)          G-43 1 1 m-chloro                                                                             fluoro                                                                             fluoro                                                                             hydrogen                                                                           β                                                                           16,16-difluoro-17-(m-chlorophenyl)          G-44 1 1 m-trifluoro-                                                                         fluoro                                                                             fluoro                                                                             hydrogen                                                                           β                                                                           16,16-difluoro-17-(m-fluoromethyl-                   methyl                   phenyl)                                     __________________________________________________________________________

                                      Table H                                     __________________________________________________________________________     ##STR257##                                                                   cis-13-PGF.sub.3.sbsb.α -type, 1,9-lactones                              ##STR258##                                                                   cis-13-5,6-dihydro-PGF.sub.3.sbsb.α -type, 1,9-lactones                  ##STR259##                                                                   2,2-difluoro-cis-13-PGF.sub.3.sbsb.α -type, 1,9-lactones                 ##STR260##                                                                   2,2-difluoro-cis-13-5,6-dihydro-PGF.sub.3.sbsb.α -type,                 1,9-lactones                                                                   ##STR261##                                                                   cis,cis-4,5,17,18-tetradehydro-cis-13-PGF.sub.1.sbsb.α -                type, 1,9-lactones                                                             ##STR262##                                                                   5-oxa-cis-13-cis-17,18-didehydro-PGF.sub.1.sbsb.α -type,                1,9-lactones                                                                   ##STR263##                                                                   4-oxa-cis-13-cis-17,18-didehydro-PGF.sub.1.sbsb.α -type                 1,9-lactones                                                                   ##STR264##                                                                   3-oxa-cis-13-cis-17,18-didehydro-PGF.sub.1.sbsb.α -type,                1,9-lactones                                                                   ##STR265##                                                                   3,7-inter-m-phenylene-4,5,6-trinor-cis-13-cis-                                17,18-didehydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                     ##STR266##                                                                   3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-cis-                                 13-cis-17,18-didehydro-PGF.sub.1.sbsb.α -type, 1,9-lactones                    L.sub.1                                                                Example                                                                            g R.sub.3                                                                            R.sub.4                                                                            R.sub.5                                                                            ˜OH                                                                        Name                                                 __________________________________________________________________________    H-1  1 methyl                                                                             hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-16-methyl                                     H-2  1 methyl                                                                             hydrogen                                                                           methyl                                                                             β                                                                           15,16-dimethyl                                       H-3  1 methyl                                                                             hydrogen                                                                           hydrogen                                                                           β                                                                           16-methyl                                            H-4  1 methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          15-epi-16,16-dimethyl                                H-5  1 methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15-epi-15,16,16-trimethyl                            H-6  1 methyl                                                                             methyl                                                                             hydrogen                                                                           β                                                                           16,16-dimethyl                                       H-7  1 fluoro                                                                             hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-16-fluoro                                     H-8  1 fluoro                                                                             hydrogen                                                                           methyl                                                                             α                                                                          15-epi-15-methyl-16-fluoro                           H-9  1 fluoro                                                                             hydrogen                                                                           hydrogen                                                                           β                                                                           16-fluoro                                            H-10 1 fluoro                                                                             fluoro                                                                             hydrogen                                                                           α                                                                          15-epi-16,16-difluoro                                H-11 1 fluoro                                                                             fluoro                                                                             methyl                                                                             α                                                                          15-epi-15-methyl-16,16-difluoro                      H-12 1 fluoro                                                                             fluoro                                                                             hydrogen                                                                           β                                                                           16,16-difluoro                                       H-13 1 hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi                                               H-14 1 hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-15-methyl                                     H-15 3 hydrogen                                                                           hydrogen                                                                           hydrogen                                                                           α                                                                          15-epi-2a,2b-dihomo                                  H-16 3 hydrogen                                                                           hydrogen                                                                           methyl                                                                             α                                                                          15-epi-2a,2b-dihomo-15-methyl                        H-17 3 methyl                                                                             methyl                                                                             hydrogen                                                                           α                                                                          15-epi-2a,2b-dihomo-16,16-dimethyl                   H-18 3 methyl                                                                             methyl                                                                             methyl                                                                             α                                                                          15-epi-2a,2b-dihomo-15,16,16-trimethyl               H-19 3 fluoro                                                                             fluoro                                                                             hydrogen                                                                           α                                                                          15-epi-2a,2b-dihomo-16,16-difluoro                   H-20 3 fluoro                                                                             fluoro                                                                             methyl                                                                             α                                                                          15-epi-2a,2b-dihomo-15-methyl-16,16-di-                                       fluoro                                               __________________________________________________________________________

APPENDIX

This appendix describes the preparation of the various prostaglandinanalogs of formula 1.

With respect to Charts S and T herein, the symbols have the samedefinition herein as in Charts A-R, except that the following additionalsymbols are employed:

Y₅ is trans--CH═CH--, cis--CH═CH--, --CH₂ CH₂ --, or --CH═CH--(Hal),wherein Hal bromo or chloro.

R₁₆ is hydrogen or --OR₉, wherein R₉ is an acyl protecting group.

R₁₈ is hydrogen or --OR₁₀, wherein R₁₀ is a blocking group.

R₂₆ is alkyl, cycloalkyl, aralkyl, phenyl, or phenyl substituted withhalogen or alkyl. M₅ is ##STR267## or a mixture of ##STR268## and##STR269##

M₆ is ##STR270##

                  Chart T                                                         ______________________________________                                                                      CCXXI                                                                         CCXXII                                           ##STR271##                                                                                                 CCXXIII                                          ##STR272##                                                                                                 CCXXIV                                           ##STR273##                                                                                                 CCXXV                                            ##STR274##                                                                                                 CCXXVI                                           ##STR275##                                                                                                 CCXXVII                                          ##STR276##                                                                    ##STR277##     or a mixture of     ##STR278##

Z₇ is the same as Z₁, except that Z₇ does not include ##STR279## or

The integer n is one or 2.

Chart S provides a method whereby the formula CCI compound istransformed to the formula CCXIX compound. The formula CCI startingmaterial is known in the art. For compounds wherein R₁₆ is --OR₉, seeNetherlands Pat. No. 7,305,817, (Derwent Farmdoc CPI No. 69717U). Forthose componds wherein R₁₆ is hydrogen see Netherlands Pat. No.7,309,856, (Dewent Farmdoc CPI No. 10095V). The transformation of theformula CCI compound to the formula CCII compound proceeds by methodsknown in the art. For example, formula CCII compounds wherein L₁includes fluoro substitution are described at Netherlands Pat. No.7,305,817, (Derwent Farmdoc CPI No. 69717U); compounds wherein L₁includes methyl substitution are described in U.S. Pat. No. 3,903,131;compounds wherein R₇ includes phenyl substituted compounds are describedin Belgian Pat. No. 804,873 (Derwent Farmdoc CPI No. 22865V); andcompounds wherein R₇ includes phenoxy substitution are described inNetherlands Pat. No. 7,306,462 (Derwent Farmdoc CPI No. 732,79U). Theformula CCIII compound is prepared from the formula CCII compound bymanipulation of the C-13 C-14 double bond. For example, this bond ishydrogenated by employing catatlyic methods employing (e.g.palladium-on-charcoal) under a hydrogen atmosphere. Further, the formulaCCIII cis-13 compound is prepared from the formula CCII trans-13compound by photoisomerization. For this purpose techniques generallyknown in the art are employed. For example, the formula CCII compound isexposed to radiation of about 3500 Angstroms until a equilibrium mixtureof trans and cis isomers capable of chromatographic separation isobtained. Finally, when a formula CCIII 14-halo compound is to beprepared, the formula CCII compound is dihalogenated, thereby preparingits 13,14-dihalo derivative, followed by dehydrohalogenation with base.Again, methods generally known in the art for preparing such vicinaldihalides (e.g. reaction with the molecular halogen) anddehydrohalogenation are employed. Thereafter, the reaction sequencewhich transforms the formula CCIII compound to the formula CCVIIcompound is known in the art. See, for example, Belgian Pat. No.817,846, (Derwent Farmdoc CPI No. 09124W) and Netherlands Pat. No.7,305,817, (Derwent Farmdoc CPI No. 69717U).

The reaction sequence of Chart S wherein the formula CCVII compound istransformed to the formula CCIX compound is likewise known in the art.See, Netherlands Pat. No. 7,305,434, (Derwent Farmdoc CPI No. 69665U).

The formula CCX compound is then prepared from the formula CCIX compoundby oxidation of the formula CCIX lactol to a lactone. Thistransformation is carried out using for example silver oxide as anoxidizing agent followed by treatment with pyridine hydrochloride. Theformula CCX lactone is then converted to the formula CCXI ether bytransformation of any free hydroxy moieties to blocking groups accordingto R₁₀, following the procedures hereinabove described for suchtransformations. Thereafter, the formula CCXII compound, (wherein n is2) is prepared from the formula CCXI compound by reduction of thelactone to a lactol as in the transformation of the formula CCVIcompound to the formula CCVII compound. This formula CCXII lactol isthen transformed successively to the formula CCXIV and formula CCXVcompound by methods again known in the art and described in NetherlandsPat. No. 7,305,817, (Derwent Farmdoc CPI No. 698717U). Alternatively,the formula CCXII compound is transformed to the formula CCXVI compoundand thereafter the formula CXXVII compound by methods described in U.S.Pat. No. 3,864,387. Thereafter, the formula CCXVIII compound is preparedby hydrolysis of any blocking groups according to R₁₀, as described inprevious charts.

Finally, the formula CXVIII compound is transformed to the correspondingformula CCXIX compound when Y₅ is --CH═C(Hal)-- by dehydrohalogenation.Procedures generally known in the art are employed.

Following the procedure of Chart S and PGF.sub.α -or 11-deoxy-PGF.sub.α-type products therein, or their R₁₀ -containing precursors therein aretransformed to corresponding PGE or 11-deoxy-PGE, PGF.sub.β, or11-deoxy-PGF.sub.β, PGA, or PGB-type compounds following the proceduresdescribed in Netherlands Pat. No. 7,305,817, (Derwent Farmdoc CPI No69717U).

In preparing 8β,12α-isomers of products described in the precedingparagraph or in Chart S, the procedures of Chart S in the precedingparagraph are employed, except that in place of the formula CCI bicycliclactone aldehyde there is employed the following compound: ##STR280##This epimeric bicyclic lactone aldehyde is described in Belgian Pat. No.804,873, (Derwent Farmdoc CPI No. 22865V), and Netherlands Pat. No.7,309,856 (Derwent Farmdoc CPI No. 10095V). Accordingly, the8β,12α-PGF.sub.β or 11-deoxy-PGF.sub.β -type product corresponding toformula CCIX is prepared. By the method referenced in the precedingparagraph this compound is likewise transformed to the correspondingPGE- or 11-deoxy-PGE-type compound, PGF.sub.α or 11-deoxy-PGF₆₀ -typecompound, PGA-type compound, or, PGB-type compound. Alternatively, thevarious 8β,12α-PG-type compounds of formula I are prepared from entPGA-type compounds. In this case, for example, the enantiomer of theformula CCI compound is employed in the preparation of an ent PGA-typecompound, which is then epoxidized and reduced to the corresponding(11RS)-8β,12α-PGE-type compound. Methods for this transformation, andthe successive transformations of (11RS)-8β,12α-PGE-type compound aredescribed in Belgian Pat. No. 804,873 (Derwent Farmdoc CPI No. 22865V).

Further PGA-type compound or ent-PGA-type compounds are transformed to11-deoxy-PGE-, 11-deoxy-PGF.sub.α -, or 11-deoxy-PGF.sub.β -typecompounds by a borohydride cyclopentane ring reduction or catalytic ringreduction by the procedure described in Netherlands Pat. No. 7,309,856,(Derwent Farmdoc CPI No. 10095V).

Prostaglandin analogs of formula I with interphenylene-orinterphenylene-oxa-containing side chains are prepared by methods knownin the art and described in U.S. Pat. No. 3,928,418. For example, ChartsL and M therein describe methods whereby interphenylene oxa compoundsare conveniently prepared from readily available starting materials. Forpreparing interphenylene-containing prostaglandin analogs, i.e. thosewherein Z₁ is ##STR281## then, the procedure of Chart M of U.S. Pat. No.3,928,418 is employed except that in step (a) of this Chart an aldehydeof the formula ##STR282## is employed in place of the specified startingmaterial therein.

For the 16-phenoxy interphenylene containing compounds, the preferredmethod of their preparation proceeds by ozonolysis of the trans-13double bond of the final PGF.sub.α final product to a corresponding13,14,15,16,17,18,19,20-octanor-13-carboxaldehyde PGF.sub.α -typeproduct. This aldehyde is then transformed to the16-phenoxy-3,7-inter-m-phenylene-or3,7-inter-m-phenylene-3-oxa-16-phenoxy-PGF.sub.α -type compound by theprocedure of chart S (e.g. the transformation affecting the 2.sub.β-side chain of the formula CI aldehyde therein).

when interphenylene or interphenylene oxa-containing prostaglandinanalogs of formula I are to be prepared wherein Y₁ is --CH₂ CH₂ --,catalytic hydrogenation methods of the corresponding trans-13 compoundare employed, as described above. When interphenylene orinterphenyleneoxa-containing prostaglandin analogs wherein Y₁ iscis--CH═CH-- or --C.tbd.C are to be prepared, then the preparation firstproceeds by oxidation of the 15-hydroxy (of compounds wherein R₅ ishydrogen) to a corresponding 15-oxo using reagents known in the art toselectively effect this reduction. For example,2,3-dichloro-5,6-dicyanobenzoquinone is employed. Thereupon, thetransformation of the α,β-unsaturated ketones so formed proceeds as inthe transformation of the formula CCII compound to the formula CCIIIcompound. Thereafter, when the 13-acetylenic moiety is to be introduced,dehydrohalogenation with base is employed. Having prepared each of thevarious PGF.sub.α -type interphenylene or interphenylene oxa-containinganalogs, transformation to the corresponding PGE-, PGF.sub.β -, PGA-,PGB, 11-deoxy-PGF.sub.α -, or 11-deoxy-PGF.sub.β -type compoundsproceeds by methods described following Chart S. Further, when8β,12α-type compounds are to be prepared the ent PGF.sub.α -typecompounds corresponding to Charts L and M are employed, beingtransformed to the corresponding ent-PGA-type compound which isthereafter transformed to the various 8β,12α-isomers of the various ringstructures described above.

Chart T provides a method whereby the various PGF.sub.α -type compoundsdescribed in and following Chart S are transformed to the variousPG-type compounds with 11-oxo-containing cyclopentane ring structures(formulas CCXXV, CCXXVI, and CCXXVII).

With respect to Chart T the transformations therein are all generallydescribed in succeeding Charts. For example, the transformation of theformula CCXXI compound to the formula CCXXII compound is accomplished bythe selective blocking described in the transformation of the formulaXXXI compound to the formula XXXIV compound of Chart B, followed by theselective silylation described in the transformation of the formula XLIcompound to the formula XLII compound of Chart C.

Thereafter, the optional epimerization of the formula CCXXII compound tothe formula CCXXIII compound proceeds as is described in thetransformation of the formula CLXII compound to the formula CLXIIIcompound in Chart M. Finally, the C-9 blocking, and selective C-11hydrolysis of the transformation of the formula CCXXIII compound to theformula CCXXIV compound is described in Chart C wherein the formulaCXLII or formula CXLIV compound is transformed to the formula CXLVIcompound. Finally, the oxidation of the formula CCXXIV compound to theformula CCXXV compound is described in the transformation of Chart C ofthe formula XLVII compound to the formula LI compound, and thereafterthe formula LII compound.

With respect to the transformation to the formula CCXXV compound to theformula CCXXVI compound the method employed in Chart F and thetransformation of the formula XCIII compound to the formula XCIVcompound is employed.

Finally, the transformation of the formula CCXXVI compound to theformula CCXXVII compound is achieved by methods described followingChart S for the transformation of PGA-type compounds corresponding11-deoxy-PGE-type compounds.

I claim:
 1. A prostaglandin-type, 1,9-lactone of the formula ##STR283## wherein W₂ is ##STR284## wherein L₁ is ##STR285## or a mixture of ##STR286## wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is fluoro, only when the other is hydrogen or fluoro;wherein M₁ is ##STR287## wherein R₅ is hydrogen or methyl; wherein R₇ is --(CH₂)_(m) --CH₃, wherein m is one to 5, inclusive, cis--CH═CH--CH₂ --CH₃, or ##STR288## wherein T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, the various T's being the same or different, s is zero, one, 2, or 3, and Z₃ is oxa or methylene, with the provisio that not more than two T's are other than alkyl, and the further proviso that Z₃ is oxa only when R₃ r₄ ₄ are hydrogen or methyl, being the same or different; wherein Y₁ is trans--CH═CH--, --CH₂ CH₂ --, cis--CH═CH--, or --C.tbd.C--; and wherein Z₁ is

    cis--CH═CH--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 --, (1)

    cis--CH═CH--CH.sub.2 --(CH.sub.2).sub.g --CF.sub.2 --, (2)

    cis--CH.sub.2 --CH═CH--(CH.sub.2).sub.g --CH.sub.2 --, (3)

    --(ch.sub.2).sub.3 --(ch.sub.2).sub.g --CH.sub.2 --,       (4)

    --(ch.sub.2).sub.3 --(ch.sub.2).sub.g --CF.sub.2 --,       (5)

    --ch.sub.2 --o--ch.sub.2 --(ch.sub.2).sub.g --CH.sub.2 --, (6) ##STR289## wherein g is one to 3, inclusive.


2. A compound according to claim 1, wherein W₂ is ##STR290##
 3. 11-Deoxy-PGF₂α, 1,9-lactone, a compound according to claim
 2. 4. A compound according to claim 1, wherein W₂ is ##STR291##
 5. A compound according to claim 4, wherein Y₁ is --C.tbd.C--.
 6. 13,14-Didehydro-PGD₂, 1,9-lactone, a compound according to claim
 5. 7. A compound according to claim 4, wherein Y₁ is cis--CH═CH--.
 8. cis-13-PGD₂, 1,9-lactone.
 9. A compound according to claim 4, wherein Y₁ is --CH₂ CH₂ --.
 10. 13,14-Dihydro-PGD₂, 1,9-lactone, a compound according to claim
 9. 11. A compound according to claim 4, wherein Y₁ is trans--CH═CH--.
 12. PGD₂, 1,9-lactone, a compound according to claim
 11. 13. A compound according to claim 1, wherein W₂ is ##STR292##
 14. A compound according to claim 13, wherein ˜ is α.
 15. A compound according to claim 14, wherein M₁ ##STR293##
 16. 15-epi-PGF₂α, 1,9-lactone, a compound according to claim
 15. 17. A compound according to claim 14, wherein M₁ is ##STR294##
 18. A compound according to claim 17, wherein Z₁ is --CH₂ --O--CH₂ --(CH₂)_(g) --CH₂ --.
 19. 5-oxa-PGF₁α, 1,9-lactone, a compound according to claim
 18. 20. A compound according to claim 17, wherein Z₁ is ##STR295##
 21. 3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁α, 1,9-lactone, a compound according to claim
 20. 22. A compound according to claim 17, wherein Z₁ is ##STR296##
 23. 3,7-inter-m-phenylene-4,5,6-trinor-PGF₁α, 1,9-lactone, a compound according to claim
 22. 24. A compound according to claim 17, wherein Z₁ is cis--CH₂ --CH═CH--(CH₂)_(g) --CH₂ --.
 25. cis-4,5-Didehydro-PGF₁α, 1,9-lactone, a compound according to claim
 24. 26. A compound according to claim 17, wherein Z₁ is cis--CH═CH--CH₂ --(CH₂)_(g) --CF₂ --.
 27. 2,2,16,16-Tetrafluoro-PGF₂α, 1,9-lactone, a compound according to claim
 26. 28. 2,2-Difluoro-16,16-dimethyl-PGF₂α, 1,9-lactone, a compound according to claim
 26. 29. 2,2-Difluoro-15-methyl-PGF₂α, 1,9-lactones, a compound according to claim
 26. 30. 2,2-Difluoro-PGF₂α, 1,9-lactone, a compound according to claim
 26. 31. A compound according to claim 17, wherein Z₁ is --(CH₂)₃ --(CH₂)_(g) --CF₂ --.
 32. 2,2,16,16-Tetrafluoro-PGF₁α, 1,9-lactone, a compound according to claim
 31. 33. 2,2-Difluoro-16,16-dimethyl-PGF₁α, 1,9-lactone, a compound according to claim
 31. 34. 2,2-Difluoro-15-methyl-PGF₁α, 1,9-lactone, a compound according to claim
 31. 35. 2,2-Difluoro-PGF₁α, 1,9-lactone, a compound according to claim
 31. 36. A compound according to claim 17, wherein Z₁ is --(CH₂)₃ --(CH₂)_(g) --CH₂ --.
 37. 16,16-Difluoro-PGF₁α, 1,9-lactone, a compound according to claim
 36. 38. 16,16-Dimethyl-PGF₁α, 1,9-lactone, a compound according to claim
 36. 39. 15-Methyl-PGF₁α, 1,9-lactone, a compound according to claim
 36. 40. PGF₁α, 1,9-lactone, a compound according to claim
 36. 41. A compound according to claim 17, wherein Z₁ is cis--CH═CH--CH₂ --(CH₂)_(g) --CH₂ --.
 42. A compound according to claim 41, wherein g is
 3. 43. A compound according to claim 41, wherein g is
 1. 44. A compound according to claim 43, wherein Y₁ is --C.tbd.C--.
 45. 13,14-Didehydro-PGF₂α, 1,9-lactone, a compound according to claim
 44. 46. A compound according to claim 43, wherein Y₁ is cis--CH═CH--.
 47. cis-13-PGF₂α, 1,9-lactone, a compound according to claim
 46. 48. A compound according to claim 43, wherein Y₁ is --CH₂ CH₂ --.
 49. 13,14-dihydro PGF₂α, 1,9-lactone, a compound according to claim
 48. 50. A compound according to claim 43, wherein Y₁ is trans--CH═CH--.
 51. A compound according to claim 50, wherein R₇ is cis--CH═CH--CH₂ --CH₃ --.
 52. PGF₃α, 1,9-lactone, a compound according to claim
 51. 53. A compound according to claim 50, wherein R₇ is ##STR297##
 54. A compound according to claim 53, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 55. A compound according to claim 54, wherein Z₃ is methylene.
 56. A compound according to claim 55, wherein R₅ is methyl.
 57. 15-Methyl-17-Phenyl-18,19,20-trinor-PGF₂α, 1,9-lactone, a compound according to claim
 56. 58. A compound according to claim 55, wherein R₅ is hydrogen.
 59. A compound according to claim 58, wherein at least one of R₃ and R₄ are fluoro.
 60. 16,16-Difluoro-17-Phenyl-18,19,20-trinor-PGF₂α, 1,9-lactone, a compound according to claim
 59. 61. A compound according to claim 58, wherein at least one of R₃ and R₄ is methyl.
 62. 16,16-Dimethyl-17-phenyl-18,19,20-trinor-PGF₂α, 1,9-lactone, a compound according to claim
 61. 63. A compound according to claim 58, wherein R₃ and R₄ are both hydrogen.
 64. 17-Phenyl-18,19,20-trinor-PGF₂α, 1,9-lactone, a compound according to claim
 63. 65. A compound according to claim 54, wherein Z₃ is oxa.
 66. A compound according to claim 65, wherein R₅ is methyl.
 67. 15-Methyl-16-Phenoxy-17,18,19,20-tetranor-PGF₂α, 1,9-lactone, a compound according to claim
 66. 68. A compound according to claim 65, wherein R₅ is hydrogen.
 69. A compound according to claim 68, wherein at least one of R₃ and R₄ is methyl.
 70. 16-Methyl-16-Phenoxy-18,19,20-trinor-PGF₂α, 1,9-lactone, a compound according to claim
 69. 71. A compound according to claim 68, wherein R₃ and R₄ are both hydrogen.
 72. 16-Phenoxy-17,18,19,20-tetranor-PGF₂α, 1,9-lactone, a compound according to claim
 71. 73. A compound according to claim 50, wherein R₇, is --(CH₂)_(m) --CH₃ --.
 74. A compound according to claim 73, wherein m is
 3. 75. A compound according to claim 74, wherein R₅ is methyl.
 76. A compound according to claim 75, wherein at least one of R₃ and R₄ is fluoro.
 77. 15-Methyl-16,16-difluoro-PGF₂α, 1,9-lactone, a compound according to claim
 76. 78. A compound according to claim 75, wherein at least one of R₃ and R₄ is methyl.
 79. 15,16,16-Trimethyl-PGF₂α, 1,9-lactone, a compound according to claim
 78. 80. A compound according to claim 75, wherein R₃ and R₄ are both hydrogen.
 81. 15-Methyl-PGF₂α, 1,9-lactone, a compound according to claim
 80. 82. A compound according to claim 74, wherein R₅ is hydrogen.
 83. A compound according to claim 82, wherein at least one of R₃ and R₄ is fluoro.
 84. A compound according to claim 83, wherein R₃ and R₄ are both fluoro.
 85. 16,16-Difluoro-PGF₂α, 1,9-lactone, a compound according to claim
 84. 86. A compound according to claim 82, wherein at least one of R₃ and R₄ is methyl.
 87. A compound according to claim 86, wherein R₃ and R₄ are both methyl.
 88. 16,16-Dimethyl-PGF₂α, 1,9-lactone, a compound according to claim
 87. 89. A compound according to claim 82, wherein R₃ and R₄ are both hydrogen.
 90. PGF₂α, 1,9-lactone, a compound according to claim
 89. 